丹皮酚抑制黑素合成相关分子机制的研究及KC-MC共培养体系中细胞因子对黑素合成的反馈调节
摘要
1本课题组先前的研究发现,中药单体丹皮酚具有较强的抑制黑素合成的活性。本文研究了丹皮酚对黑素合成限速酶-Tyr的活性、mRNA和蛋白表达的影响,及对Tyr启动子配体小眼畸形转录因子(MITF)和MITF启动子配体cAMP反应元件结合蛋白(CREB)磷酸化表达的影响。
本研究首次表明,丹皮酚可以通过抑制CREB的磷酸化,使其不活化,抑制MITF的转录,进而下调Tyr的转录以及表达,最终影响黑素合成。本研究结果有助于理解丹皮酚抗黑素合成的作用机制,有利于研究和筛选抗黑素沉着异常的药物。
2我们研究了丹皮酚抑制黑素合成的信号转导途径,以进一步探讨丹皮酚美白功效的分子机制。
研究结果表明,JNK1/2/3特异性抑制剂SP600125能够拮抗丹皮酚对黑素合成的抑制作用,包括黑素含量、Tyr活性及其mRNA和蛋白表达等多个指标;同时发现丹皮酚能够上调磷酸化JNK/SAPK的表达,而对磷酸化ERK和p38MAPK均无影响。表明在B16F10细胞内,丹皮酚可以激活MAPK家族的JNK/SAPK信号转导途径,从而减少黑素合成。而该家族的ERK1/2以及p38MAPK信号转导途径未参与介导丹皮酚的作用。
根据上述结果,我们推测丹皮酚的作用机制是:丹皮酚激活了JNK/SAPK激酶,活化了JNK/SAPK途径,该途径的活化直接或间接激活了某种磷酸化酶,从而使磷酸化的CREB去磷酸化,下调MITF表达,进而减少Tyr表达,抑制黑素合成。
在B16F10小鼠黑素瘤细胞系内,有关JNK/SAPK参与介导化学物质对黑素合成的调节作用尚未见报道。
另外,我们的研究表明,cAMP/PKA特异性激动剂IBMX和抑制剂H89能分别拮抗和加剧丹皮酚对黑素合成的抑制作用。提示cAMP/PKA途径可能也参与了介导丹皮酚的抑制黑素合成作用。由于cAMP/PKA途径的激活本身对黑素合成具有上调作用,所以对该途径在丹皮酚确切作用机制有待进一步研究。
对丹皮酚抑制黑素合成以及相关信号转导途径的研究有助于理解丹皮酚的作用机制,包括丹皮酚在其它疾病中的治疗机制。并为其用于治疗某些色素沉着异常性疾病提供了实验依据,有助于更全面地理解黑素合成机制以及色素异常性疾病的发病机制。
3本课题组的前期研究发现丹皮酚在单独的MC以及KC-MC共培养模型中的抗黑素合成作用有明显差异,对共培养模型中黑素合成的抑制作用弱于对MC细胞中抑制作用,提示丹皮酚可能通过KC细胞间接影响MC细胞,从而削弱了其对黑素合成的抑制作用。因此我们利用单独KC、MC培养以及KC-MC共培养模型进一步研究这种差异的可能原因。KC细胞主要通过其分泌的细胞因子调节(主要包括ET-1和sSCF等)调节MC的黑素合成。在本研究中,我们利用已知的能够影响黑素合成的药物(HQ、丹皮酚、8-MOP、L-酪氨酸、熊果苷和烟酰胺)作用于单独KC、MC培养以及KC-MC共培养模型,检测不同药物作用后,单独培养的KC细胞模型和KC-MC共培养模型中ET-1和sSCF水平的变化,从而探讨MC单细胞模型和KC—MC共培养模型对药物作用产生不同反应的可能原因,并为探讨黑素合成反馈机制提供基础。
研究结果表明,正是由于KC的存在,使得干预物对单独MC模型和KC-MC共培养模型中黑素合成的作用出现了明显的差异。药物作用72h后检测发现,在KC-MC共培养模型中,HQ可以同时显著减少KC合成ET-1和sSCF;而熊果苷虽然在抑制KC合成sSCF上和HQ作用相当,但是其对ET-1的抑制作用不如HQ;而丹皮酚对模型合成ET-1和sSCF则均无影响。同样作为促黑素合成干预物,酪氨酸可以促进细胞因子ET-1分泌,而8-MOP反而抑制了共培养模型合成ET-1。以上结果提示在共培养模型中,KC在一定程度上影响着药物对黑素合成的作用,而这种作用可以是拮抗的也可以是协同的,很大程度上取决于药物在共培养模型中对KC的影响,这种影响可能和药物本身的生物活性相关。说明在研究、筛选和开发抗色素异常性疾病的治疗药物时,选择KC-MC共培养模型比单一MC培养模型更能反映被选化合物的活性。该结果对指导新药研发具有一定意义。
同时,通过对单独KC模型和KC-MC模型的比较,我们发现了一个有趣的现象:8-MOP对共培养模型中ET-1合成有抑制作用,但是在单独培养的KC细胞模型中,8-MOP作用72h时ET-1和sSCF均无明显改变(p＞0.05),提示8-MOP对共培养模型中ET-1的影响不是通过直接抑制KC完成的,而可能是通过其对MC的作用间接影响ET-1。为进一步研究黑素沉着中的反馈机制提供了思路。
4筛选了10、20和50μM浓度的8-MOP作为正相的干扰信息(增加黑素合成)。筛选10和20μM浓度的PTU作为负相的干扰信息(减少黑素合成),利用此两种药物作为干扰信息,结合KC-MC共培养模型我们构建了一个闭环系统,检测并分析了72h后模型内黑素含量(输出变量)的改变和模型内细胞因子ET-1和sSCF(反馈信息)变化的关系。结果表明,变量黑素的改变影响了体系内ET-1的水平,各组的ET-1水平和黑素含量形成明显负相关(r=-0.858),并证明ET-1能够促进黑素合成,结果论证了KC-MC共培养体系中反馈调节机制的存在。
本研究得出了关于黑素沉着的新的机制,即由MC、KC、黑素以及KC源性细胞因子构成的一个完整的反馈体系:KC通过自身分泌的细胞因子调节黑素沉着,当环境刺激(干扰信息)作用于MC(控制系统)时,MC合成并转运到KC内的黑素的量(输出变量)发生改变,KC(受控系统)感受到了这种改变,产生或减少细胞因子ET-1的合成分泌(反馈信息),反馈信息作用于MC,从而调节黑素合成。
由此可推测,在表皮内的表皮黑素单位中,MC合成黑素并转运到KC,而KC通过自身分泌的细胞因子调节MC,MC通过所合成的黑素调节KC分泌细胞因子,以达到局部内环境的平衡。这种调控应答外界环境及干扰物对黑素沉着的调节。当某种外界因素(在一定的范围之内)作用于表皮黑素单位时,机体启动反馈调节机制,使黑素沉着保持在一定的水平。当刺激过强时,超出反馈控制系统的调节能力,原有的平衡被打破,黑素沉着产生异常。
本研究提出并论证了黑素沉着中反馈控制系统及反馈调节机制的存在,对黑素沉着整体机制形成了必要的补充,有助于更全面地了解皮肤生理及色素异常性皮肤病的发病机理;并对临床用药有一定的指导意义。
1 Paeonol,which is Chinese traditional medicine,has been proved to have a new function:inhibition of melanogenesis.Tyrosinase and its transcriptional regulator microphthalmia-associated transcription factor(MITF) play critical roles in regulation of melanogenesis,and are required for environmental cues or agents in modulation of melanin synthesis.In this report,we discovered that paeonol down-regulated melanin production via decreasing MITF expression and consequent mRNA and protein levels of tyrosinase.We also found that paeonol reduced phosphorylation of a cAMP responsive element binding protein (phospho-CREB),which binds and activates MITF.
This research contributes to understanding the mechanism of inhibition by paeonol in B16F10 melamoma ceils.
2 Identifying the signals mediating the effects of paeonol on melanogenesis is crucial to understanding how pigmentation responds to paeonol.Resultes showed that a selective inhibitor of c-jun N-terminal or stress-activated protein kinases(JNK/SAPK)-SP600125 significantly reversed paeonol-induced down-regulation of melanin synthesis.Inhibition of cAMP/PKA pathway intensified the hypopigmentation response to paeonol.These results identify a mechanism in which paeonol induces the down-regulation of melanogenesis through inhibition of CREB phosphorylation,leading to the expression reduction of MITF and subsequently tyrosinase.The key kinase mediating the effects of paeonol on melanogenesis in B16F10 cells is JNK/SAPK.Additionally,the cAMP/PKA pathway may take part in this process.
Base on the two results,we conclude that melanogenesis inhibited by paeonol may be mediated by an unknown phosphorylase activated by JNK/SAPK pathway,and inhibiting phosphorylation of CREB and expression of MITF, consequent level of tyrosinase and melanin synthesis.
The mediation of JNK/SAPK in pigmentation induced by chemicals has not been reported.
The study on the key proteins,enzymes and signaling transduction pathways mediating the inhibition of melanogenesis by paeonol conduces to understanding the mechanism of paeonal on hypopigmentation,and contributes to the apply of the paeonol on pigmentary disorders in future.And it is also useful for the research on mechanism of pigmentation.
3 In our prior researches,significant difference was found in the levels of inhibition on pigmentation by paeonol in MC culture and co-culture model.And the decreasing of melanogenesis in co-culture model was more obvious than that in MC culture cells.The phenomenon suggests that except for the direct effect on MC,paeonol may also act on KC,then influence on the melanogenesis indirectly. It is already kown that KC play a key role in regluating epidermal pigmentation by cytokines such as endothelin-1(ET-1) and stem cell factor(SCF) in paracrine way.Both of the two cytokines play important roles in melanin synthesis and proliferation of MC.We detected the levels of ET-1 and sSCF in KC and co-culture models after treated with classic regulators including melanogenesis agonists like HQ,and antagonists such as 8-MOP,in order to analysis the mechanism of different reactions to stimulators in single cell culture and co-culture model.Results showed that the vary effects on KC by different regulators is the main reason of different status of melanogenesis in two kinds of models.The effects on KC could be synergetic or antagonistic,which mainly dependes on the activity and/or dose of regulators.It shows that the KC-MC coculture model is more suitable for screening,studying the medicines applyed to clinical treatment.
4 At the same time,significant difference was found in the levels of cytokines ET-1 and sSCF under stimulation of interferents in two models,although the number of cells were the same.For example,8-MOP in co-culture model inhibited the level of ET-1 with no effect on the level of ET-1 in KC model.We know 8-MOP is the antagonist of melanogenesis,and the finding suggests that the inhibition of ET-1 may result from the increasing of melanin induced by 8-MOP.What kind of interaction is it between the two cytes? Is it regulated by feedback mechanism?
Because of close to the physiological environment of skin,the co-culture model is the suitable subject for us to study the interaction between KC and MC. Using co-culture model and specific regulators which affect melanin synthesis without effect on cytokines paracrined by KC,we set up an close loop system-feedback system,which is necessary for studying feedback mechanism. Negative correlation was proved between the melanin content and the concentration of ET-1 in co-culture model.And ET-1 is able to improve the melanin synthesis simultaneously.Base on the two results,we initially demonstrated that the feedback mechanism exists between MC and KC and regulates the pigmenattion to some extent.
Summarily,the KC,MC,melnin and cytokines consist the total feedback system,in which the KC regulates the pigmentation by cytokines,when the MC is stimulated by environmental factors,the content of melanin transferred into KC changes,then KC regulates its cytokines' synthesis and secretion to adjust the pigmentation.
Furthermore it suggests that in epidermal melanin unit,KC regulates the melanin synthesis by cytokines and MC regulates the cytokines secreted by melanogenesis,and it is an balancing feedback system.When there is a strong stimulators which exceeds the regulation of system,the feedback has no fuctions, so the balance is broken,abnormal pigmentation happens consequently.
It is the first time to initiate and demonstrate the feedback mechanism existing in co-culture model.This research is an important part of the complete pigmentation theory,and it can help us to understand the pathogenesis of pigmentary diseases and to find new targets for treatment.
本研究首次表明,丹皮酚可以通过抑制CREB的磷酸化,使其不活化,抑制MITF的转录,进而下调Tyr的转录以及表达,最终影响黑素合成。本研究结果有助于理解丹皮酚抗黑素合成的作用机制,有利于研究和筛选抗黑素沉着异常的药物。
2我们研究了丹皮酚抑制黑素合成的信号转导途径,以进一步探讨丹皮酚美白功效的分子机制。
研究结果表明,JNK1/2/3特异性抑制剂SP600125能够拮抗丹皮酚对黑素合成的抑制作用,包括黑素含量、Tyr活性及其mRNA和蛋白表达等多个指标;同时发现丹皮酚能够上调磷酸化JNK/SAPK的表达,而对磷酸化ERK和p38MAPK均无影响。表明在B16F10细胞内,丹皮酚可以激活MAPK家族的JNK/SAPK信号转导途径,从而减少黑素合成。而该家族的ERK1/2以及p38MAPK信号转导途径未参与介导丹皮酚的作用。
根据上述结果,我们推测丹皮酚的作用机制是:丹皮酚激活了JNK/SAPK激酶,活化了JNK/SAPK途径,该途径的活化直接或间接激活了某种磷酸化酶,从而使磷酸化的CREB去磷酸化,下调MITF表达,进而减少Tyr表达,抑制黑素合成。
在B16F10小鼠黑素瘤细胞系内,有关JNK/SAPK参与介导化学物质对黑素合成的调节作用尚未见报道。
另外,我们的研究表明,cAMP/PKA特异性激动剂IBMX和抑制剂H89能分别拮抗和加剧丹皮酚对黑素合成的抑制作用。提示cAMP/PKA途径可能也参与了介导丹皮酚的抑制黑素合成作用。由于cAMP/PKA途径的激活本身对黑素合成具有上调作用,所以对该途径在丹皮酚确切作用机制有待进一步研究。
对丹皮酚抑制黑素合成以及相关信号转导途径的研究有助于理解丹皮酚的作用机制,包括丹皮酚在其它疾病中的治疗机制。并为其用于治疗某些色素沉着异常性疾病提供了实验依据,有助于更全面地理解黑素合成机制以及色素异常性疾病的发病机制。
3本课题组的前期研究发现丹皮酚在单独的MC以及KC-MC共培养模型中的抗黑素合成作用有明显差异,对共培养模型中黑素合成的抑制作用弱于对MC细胞中抑制作用,提示丹皮酚可能通过KC细胞间接影响MC细胞,从而削弱了其对黑素合成的抑制作用。因此我们利用单独KC、MC培养以及KC-MC共培养模型进一步研究这种差异的可能原因。KC细胞主要通过其分泌的细胞因子调节(主要包括ET-1和sSCF等)调节MC的黑素合成。在本研究中,我们利用已知的能够影响黑素合成的药物(HQ、丹皮酚、8-MOP、L-酪氨酸、熊果苷和烟酰胺)作用于单独KC、MC培养以及KC-MC共培养模型,检测不同药物作用后,单独培养的KC细胞模型和KC-MC共培养模型中ET-1和sSCF水平的变化,从而探讨MC单细胞模型和KC—MC共培养模型对药物作用产生不同反应的可能原因,并为探讨黑素合成反馈机制提供基础。
研究结果表明,正是由于KC的存在,使得干预物对单独MC模型和KC-MC共培养模型中黑素合成的作用出现了明显的差异。药物作用72h后检测发现,在KC-MC共培养模型中,HQ可以同时显著减少KC合成ET-1和sSCF;而熊果苷虽然在抑制KC合成sSCF上和HQ作用相当,但是其对ET-1的抑制作用不如HQ;而丹皮酚对模型合成ET-1和sSCF则均无影响。同样作为促黑素合成干预物,酪氨酸可以促进细胞因子ET-1分泌,而8-MOP反而抑制了共培养模型合成ET-1。以上结果提示在共培养模型中,KC在一定程度上影响着药物对黑素合成的作用,而这种作用可以是拮抗的也可以是协同的,很大程度上取决于药物在共培养模型中对KC的影响,这种影响可能和药物本身的生物活性相关。说明在研究、筛选和开发抗色素异常性疾病的治疗药物时,选择KC-MC共培养模型比单一MC培养模型更能反映被选化合物的活性。该结果对指导新药研发具有一定意义。
同时,通过对单独KC模型和KC-MC模型的比较,我们发现了一个有趣的现象:8-MOP对共培养模型中ET-1合成有抑制作用,但是在单独培养的KC细胞模型中,8-MOP作用72h时ET-1和sSCF均无明显改变(p＞0.05),提示8-MOP对共培养模型中ET-1的影响不是通过直接抑制KC完成的,而可能是通过其对MC的作用间接影响ET-1。为进一步研究黑素沉着中的反馈机制提供了思路。
4筛选了10、20和50μM浓度的8-MOP作为正相的干扰信息(增加黑素合成)。筛选10和20μM浓度的PTU作为负相的干扰信息(减少黑素合成),利用此两种药物作为干扰信息,结合KC-MC共培养模型我们构建了一个闭环系统,检测并分析了72h后模型内黑素含量(输出变量)的改变和模型内细胞因子ET-1和sSCF(反馈信息)变化的关系。结果表明,变量黑素的改变影响了体系内ET-1的水平,各组的ET-1水平和黑素含量形成明显负相关(r=-0.858),并证明ET-1能够促进黑素合成,结果论证了KC-MC共培养体系中反馈调节机制的存在。
本研究得出了关于黑素沉着的新的机制,即由MC、KC、黑素以及KC源性细胞因子构成的一个完整的反馈体系:KC通过自身分泌的细胞因子调节黑素沉着,当环境刺激(干扰信息)作用于MC(控制系统)时,MC合成并转运到KC内的黑素的量(输出变量)发生改变,KC(受控系统)感受到了这种改变,产生或减少细胞因子ET-1的合成分泌(反馈信息),反馈信息作用于MC,从而调节黑素合成。
由此可推测,在表皮内的表皮黑素单位中,MC合成黑素并转运到KC,而KC通过自身分泌的细胞因子调节MC,MC通过所合成的黑素调节KC分泌细胞因子,以达到局部内环境的平衡。这种调控应答外界环境及干扰物对黑素沉着的调节。当某种外界因素(在一定的范围之内)作用于表皮黑素单位时,机体启动反馈调节机制,使黑素沉着保持在一定的水平。当刺激过强时,超出反馈控制系统的调节能力,原有的平衡被打破,黑素沉着产生异常。
本研究提出并论证了黑素沉着中反馈控制系统及反馈调节机制的存在,对黑素沉着整体机制形成了必要的补充,有助于更全面地了解皮肤生理及色素异常性皮肤病的发病机理;并对临床用药有一定的指导意义。
1 Paeonol,which is Chinese traditional medicine,has been proved to have a new function:inhibition of melanogenesis.Tyrosinase and its transcriptional regulator microphthalmia-associated transcription factor(MITF) play critical roles in regulation of melanogenesis,and are required for environmental cues or agents in modulation of melanin synthesis.In this report,we discovered that paeonol down-regulated melanin production via decreasing MITF expression and consequent mRNA and protein levels of tyrosinase.We also found that paeonol reduced phosphorylation of a cAMP responsive element binding protein (phospho-CREB),which binds and activates MITF.
This research contributes to understanding the mechanism of inhibition by paeonol in B16F10 melamoma ceils.
2 Identifying the signals mediating the effects of paeonol on melanogenesis is crucial to understanding how pigmentation responds to paeonol.Resultes showed that a selective inhibitor of c-jun N-terminal or stress-activated protein kinases(JNK/SAPK)-SP600125 significantly reversed paeonol-induced down-regulation of melanin synthesis.Inhibition of cAMP/PKA pathway intensified the hypopigmentation response to paeonol.These results identify a mechanism in which paeonol induces the down-regulation of melanogenesis through inhibition of CREB phosphorylation,leading to the expression reduction of MITF and subsequently tyrosinase.The key kinase mediating the effects of paeonol on melanogenesis in B16F10 cells is JNK/SAPK.Additionally,the cAMP/PKA pathway may take part in this process.
Base on the two results,we conclude that melanogenesis inhibited by paeonol may be mediated by an unknown phosphorylase activated by JNK/SAPK pathway,and inhibiting phosphorylation of CREB and expression of MITF, consequent level of tyrosinase and melanin synthesis.
The mediation of JNK/SAPK in pigmentation induced by chemicals has not been reported.
The study on the key proteins,enzymes and signaling transduction pathways mediating the inhibition of melanogenesis by paeonol conduces to understanding the mechanism of paeonal on hypopigmentation,and contributes to the apply of the paeonol on pigmentary disorders in future.And it is also useful for the research on mechanism of pigmentation.
3 In our prior researches,significant difference was found in the levels of inhibition on pigmentation by paeonol in MC culture and co-culture model.And the decreasing of melanogenesis in co-culture model was more obvious than that in MC culture cells.The phenomenon suggests that except for the direct effect on MC,paeonol may also act on KC,then influence on the melanogenesis indirectly. It is already kown that KC play a key role in regluating epidermal pigmentation by cytokines such as endothelin-1(ET-1) and stem cell factor(SCF) in paracrine way.Both of the two cytokines play important roles in melanin synthesis and proliferation of MC.We detected the levels of ET-1 and sSCF in KC and co-culture models after treated with classic regulators including melanogenesis agonists like HQ,and antagonists such as 8-MOP,in order to analysis the mechanism of different reactions to stimulators in single cell culture and co-culture model.Results showed that the vary effects on KC by different regulators is the main reason of different status of melanogenesis in two kinds of models.The effects on KC could be synergetic or antagonistic,which mainly dependes on the activity and/or dose of regulators.It shows that the KC-MC coculture model is more suitable for screening,studying the medicines applyed to clinical treatment.
4 At the same time,significant difference was found in the levels of cytokines ET-1 and sSCF under stimulation of interferents in two models,although the number of cells were the same.For example,8-MOP in co-culture model inhibited the level of ET-1 with no effect on the level of ET-1 in KC model.We know 8-MOP is the antagonist of melanogenesis,and the finding suggests that the inhibition of ET-1 may result from the increasing of melanin induced by 8-MOP.What kind of interaction is it between the two cytes? Is it regulated by feedback mechanism?
Because of close to the physiological environment of skin,the co-culture model is the suitable subject for us to study the interaction between KC and MC. Using co-culture model and specific regulators which affect melanin synthesis without effect on cytokines paracrined by KC,we set up an close loop system-feedback system,which is necessary for studying feedback mechanism. Negative correlation was proved between the melanin content and the concentration of ET-1 in co-culture model.And ET-1 is able to improve the melanin synthesis simultaneously.Base on the two results,we initially demonstrated that the feedback mechanism exists between MC and KC and regulates the pigmenattion to some extent.
Summarily,the KC,MC,melnin and cytokines consist the total feedback system,in which the KC regulates the pigmentation by cytokines,when the MC is stimulated by environmental factors,the content of melanin transferred into KC changes,then KC regulates its cytokines' synthesis and secretion to adjust the pigmentation.
Furthermore it suggests that in epidermal melanin unit,KC regulates the melanin synthesis by cytokines and MC regulates the cytokines secreted by melanogenesis,and it is an balancing feedback system.When there is a strong stimulators which exceeds the regulation of system,the feedback has no fuctions, so the balance is broken,abnormal pigmentation happens consequently.
It is the first time to initiate and demonstrate the feedback mechanism existing in co-culture model.This research is an important part of the complete pigmentation theory,and it can help us to understand the pathogenesis of pigmentary diseases and to find new targets for treatment.
引文
1.傅国强,马鹏程等.196味中药乙醇提取物对酪氨酸酶的抑制作用。中华皮肤科杂志,2003,2(36):103-10.
2.Xie Sh,Chen ZQ,and Ma PC.Down-regulation of melanin synthesis and transfer by paeonol and its mechanisms[J].The American Journal of Chinese Medicine(AJCM).2007,35(1):141-153.
3.解士海,陈志强,马鹏程,卜今等.人表皮黑素细胞与角质形成细胞共培养体外模型中黑素小体转运的观察.临床皮肤科杂志.2006;35(5):286-288.
4.Hara M,Yaar M,Gilchrest BA.Endothelinol of keratinocyte origin is a mediator of melanocyte dendricity.J Invest Dermatol.1995.105(6):744-8.
5.Luo D,Chen H,Searles G,et al.Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanin pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R.Melanoma Res.1995.5(5):303-9.
6.Brenner M,Degitz K,Besch R and Berking C.Differential expression of melanoma-associated growth factors in keratinocytes and fibroblasts by ultraviolet A and ultraviolet B radiation.British J Dermatol.2005.153:733-739.
7.Akira Hachiya,Akemi Kobayashi,Yasuko Yoshida,and et al.Biphasic Expression of Two Paracrine Melanogenic Cytokines,Stem Cell Factor and Endothelin-1,in Ultraviolet B-Induced Human Melanogenesis.American Journal of Pathology.2004.165(6):2099-2109.
8.Tada A,Sukuki I,Im S,et al.Endotherlin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation.Cell Growth Differentiation.1998,9:575-584
9.傅国强,马鹏程等.196味中药乙醇提取物对酪氨酸酶的抑制作用。中华皮肤科杂志,2003,2(36):103-106
10.Xie SH,Chen ZQ,and Ma PC.Down-regulation of melanin synthesis and transfer by paeonol and its mechanisms [J]. The American Journal of Chinese Medicin e (AJCM). 2007,35(1): 141-153.
11. Kageyama A, Oka M, Okada T. Down-regulation of melanogenesis by phospholipase D2 through ubiquitin proteasome-mediated degradation of tyrosinase[J]. J. Biol. Chem. 2004,279(26): 27774-27780.
12. Kim DS, Jeong YM, Park IK, et al. Anew 2-Imino-l,3-thiazoline derivative, KHG22394, inhibits melanin synthesis in mouse B16F10 melanoma cells[J]. Biol. Pharm. Bull. 2007,30(1): 180-183.
13. Lin CB, Babiarz L, Liebel F, et al. Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation [J]. J Invest Dermatol. 2002,119(6): 1330-40.
14. Vance K and Goding CR. The transcription network regulating melanocyte development and melanoma[J]. Pigment Cell Res. 2004,17:318-325.
15. Widlund HR and Fisher DE. Microphthalmia-associated transcription factor: a critical regulator of pigment cell development and survival [J]. Oncogene. 2003,22:3035-3041.
16. Tachibana M. Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A[J]. Pigment Cell Res. 1997,10: 25-33.
17. Fuse, N., K. Yasumoto, H. Suzuki, et al. Identification of a melanocyte-type promoter of the microphthalmia-associated transcription factor gene. Biochem. Biophys. Res. Commun. 1996.219: 702 707.
18. Land EJ and Riley PA. Spontaneous redox reactions of dopaquinone and the balance between the eumelanic and phaeomelanic pathways [J]. Pigment Cell Research.2000,13(4): 273-277.
19. Price ER, Horstmann MA, Wells AG, et al. Alpha-melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg Syndrome[J]. J Biol Chem. 1998,273(49): 33042-33047.
20. Bertolotto, C, P. Abbe, T.J. Hemesath, K. et al. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.J.Cell Biol.1998.142:827 835.
21.Hemesath,T.J.,E.R.Price,C.Takemoto,T.et al.MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes.Nature1998.391:298 - 301
22.Wu,M.,T.J.Hemesath,C.M.Takemoto,M.A.et al.c-Kit triggers dual phosphorylations,which couple activation and degradation of the essential melanocyte factor Mi.Genes 14:301 - 312,2000.
23.陈晓宇,陈明,李俊.MAPKs信号转导在类风湿性关节炎滑膜细胞中作用.中国药理学通报,2006 12:1424-1428.
24.廖清船,肖洲生,秦艳芳,刘亭,等.植物雌激素金雀异黄酮通过p38MAP通路促进骨髓间充质干细胞向成骨细胞分化.中国药理学通报,2006,06:683-687.
25.袁辉,杨胜,周文霞,等.MAPK级联信号通路与长时程增强[J].中国药理学通报,2006,22(7):769-74.
26.Kim,D.S.,S.H.Park,S.B.Kwon,E.S.Park,C.H.Huh,S.W.Youn and K.C.Park.Sphingosylphosph orylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes.Pigment Cell Res.19:146 - 153,2005.
27.Choi,H.,S.Ahn,B.G.Lee,I.Chang and J.S.Hwang.Inhibition of skin pigmentation by an extract of Lepidium apetalum and its possible implication in IL-6 mediated signaling.Pigment Cell Res.18:439 - 446,2005.
28.Kim,D.S.A new 2-imino-l,3-thiazoline derivative,KHG22394,inhibits melanin synthesis in mouse B16 melanoma cells.Biol.Pharm.Bull,30(1):180-183,2007.
29.Saha,B.,S.K.Singh,C.Sarkar,R.Bera,J.Ratha,D.J.Tobin and R.Bhadra.Activation of the Mitf promoter by lipid-stimulated activation of p38-stress signalling to CREB.Pigment Cell Res.19:595 - 605,2006.
30.Tada,A.,E.Pereira,D.Beitner-Johnson,R.Kavanagh and Z.A.Abdel-Malek.Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes.J.Invest.Dermatol.118:316 - 322,2002.
31.Smalley,K.and T.Eisen.The involvement of p38 mitogenactivated protein kinase in the a-melanocyte stimulating hormone(aMSH)-induced melanogenic and anti-proliferative effects in B16 melanoma cells.FEBS Lett.476:198 - 202,2000.
32.Mansky,K.C.,U.Sankar,J.Han and M.C.Ostrowski.Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling.J.Biol.Chem.277:11077-11083,2002.
33.Mengeaud V and Ortonne JP.Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in murine melanoma cells.Pigment Cell Res.1994.7:245-254.
34.雷铁池,朱文远。与表皮黑素细胞增殖和黑素生成相关的信号转导。国外医学皮肤性病学分册。1999,25(1):32-35.
35.Yoon H S,Lee S R,Ko H C,et al.Involvement of extracellular signal-regulated kinase in nobiletin-induced melanogenesis in murine B16/F10 melanoma cells.Biosci Biotechnol Biochem,2007,71(7):1781-4.
36.Park S H,Kim D S,Kim W G,et al.Terrein:a new melanogenesis inhibitor and its mechanism.Cell Mol Life Sci,2004,61(22):2878-85.
37.Kim D S,Park S H,Kwon S B,et al.Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes[J].Pigment Cell Res,2005,19:146-53.
38.Hirata N,Naruto S,Ohguchi K,et al.Mechanism of the melanogenesis stimulation activity of(-)-cubebin in murine B16 melanoma cells[J].Bioorg Med Chem,2007,15(14):4897-902.
39.Yanagisawa M,Kurihara H,Kimura S,and et al.A novel peptide vasoconstrictor,endothelin,is produced by vascular endothelium and modulates smooth muscle Ca2_ channels.Nature 1988,322:411-415.
40.Inoue A,Yanagisawa M,Kimura S,et al.The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. Proc Natl Acad Sci USA .1989, 86:2863-2867.
41. M. Okazaki, K. Yoshimura, G. Uchida and K. HariiCorrelation between age and the secretions of melanocyte-stimulating cytokines in cultured keratinocytes and fibroblasts. British J of Dermatol. 2005. 153(suppl 2): 23-29.
42. Akira Hachiya, Akemi Kobayashi, Yasuko Yoshida, and et al. Biphasic Expression of Two Paracrine Melanogenic Cytokines, Stem Cell Factor and Endothelin-1, in Ultraviolet B-Induced Human Melanogenesis. American Journal of Pathology. 2004.165(6): 2099-2109.
43. Kadono S, Manaka Izumi, Kawashima M, and et al. The role of the epidermal endothelin cascade in the hyperpigmnetation mechanism of Lentigo Senilis. J Invest Dermatol. 2001.116(4): 571-577.
44. Kunisada T, Lu SZ, Yoshida H, and et al. Murine cutaneous mastocytosis and epidermal melanocytosis induced by kerationcyte expression of transgenic stem cell factor. J Exp Med. 1998.187(10): 1565-1573.
45. Giebel LB, Spritz RA.. Mutation of the KIT (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. Proc Natl Acad Sci USA 1991. 88:8696-8699.
46. Fleischman RA, Saltman DL, Stastny V, Zneimer S.. Deletion of the c-kit protooncogene in the human developmental defect piebald trait. Proc Natl Acad Sci USA. 1991.88:10885-10889.
47. Lee AY, Kim AH, Choi WI, and Youm YH. Less keratinocyte-derived factor related to more keratinocyte apoptosis in depigmented than normally pigmented suction-blistered epidermis may cause passive melanocyte death in vitiligo. J Invest Dermatol. 2005. 124976-983.
48. Moretti S, Spallanzani A, Amato L, and et al. New insights into the pathogenesis of vitiligo: Imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res. 2002. 15:87-92.
49. Grabbe J, Welker P, Rosenbach T, et al: Release of stem cell factor from a human keratinocyte line, HaCaT, is increased in differentiating versus proliferating cells. J Invest Dermatol. 1996.107:219-224.
50. Hachiya A, Kobayashi A, Ohuchi A, Takema Y, Imokawa G: The paracrine roleof stem cell factor/c-kit signaling in the activation of human melanocytes in ultraviolet-B-induced pigmentation. J Invest Dermatol. 2001. 116:578-586.
51. Kunisada T, Lu SZ, Yoshida H, et al: Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J Exp Med. 1998.187:1565-1573.
52. Genji Imokawa. Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res. 2004. 17:96-110.
53. Welker P, Grabbe J, Gibbs B, Zuberbier T, Henz BM: Human mast cells produce and differentially express both soluble and membrane-bound stem cell factor. Scand J Immunol. 1999.49:495-500.
54. Jurgen Grabbe, Pia Welker, Thomas Rosenbach, et al. Release of Stem Cell Factor from a Human Keratinocyte Line, HaCat, Is Increased in Differentiating versus Proliferating Cells. The Journal of Investigative Dermatology. 1996, 107(2): 219-224.
55. Hidehiko Baba, Hideyo Uchiwa and Shinichi Watanabe. UVB Irradiation Increases the Release of SCF from Human Epidermal Cells.The Journal of Investigative Dermatology. 2004,124(5): 1075-1077.
56. Kadono S, Manaka I, Kawashima M, at al. The role of the epidermal endothelin cascade in the hyperpigmentation mechanism of Lentigo Senilis. J Invest Dermatol. 2001,116:571-577.
57. Palumbo A, d'Ischia M, Misuraca G, Prota G. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. 1991 23;1073(1):85-90.
58.Smith CI,et al. Selective cytotoxicity of hydroquinone for melanocyte-derived cells is mediated by tyrosinase activity but independent of melanin content. Pigment Cell Res, 1988,1(6): 386-9.
59.王大光等。淫羊藿苷抑制正常黑素细胞黑素合成的研究。临床皮肤科杂志,2004,33(8):460-462。
60.Chakraborty AK,Funasaka Y,Komoto M,Ichihashi M.Effect of arbutin on melanogenic proteins in human melanocytes.Pigrnent Cell Res.1998,11(4):206-12.
61.丁国斌陈璧等.熊果苷对体外培养的人黑素细胞的作用.第四军医大学学.2001.22(20):1846-1848.
62.SUGIMOTO,Takahisa NISHIMURA,Koji NOMURA,and et al.Inhibitory Effects of a-Arbutin on Melanin Synthesis in Cultured Human Melanoma Cells and a Three-Dimensional Human Skin Model Kazuhisa Biol.Pharm.Bull.27(4)510-514(2004)
63.解士海。人表皮黑素细胞-角质形成细胞共培养及11种化合物对黑素沉着的影响研究。中国协和医科大学,中国医学科学院博士研究生论文。2006。
64.Kamat JP,Devasagayam TP.Nicotinamide(vitamin B3) as an effective antioxidant against oxidative damage in rat brain mitochondria.Redox Rep.1999,4(4):179-84.
65.Chen CF,Wang D,Hwang CP,Liu HW.The protective effect of niacinamide on ischemia-reperfusion-induced liver injury.J Biomed Sci.2001Nov-Dec;8(6):446-52.
66.Hakozaki T et al.The Effect of Niacinamide On Reducing Cutaneous Pigmentation and Suppression of Melanosome Transfer.British J Dermatol,2002,147:20-31.
67.Lei TC,Virador VM,Vieira WD,et al.A melanocyte-keratinocyte co-culture model to assess regulators of pigmentation in vitro.Analytical Biochemistry,2002,305:260-268.
68.Yang SX,Mortari AP,Shukla M,et al.Exuberant Inflammation in Nicotinamide Adenine Dinucleotide Phosphate-Oxidase-Deficient Mice After Allogeneic Marrow Transplantation.The Journal of Immunology.2002,168:5840-5847.
69.J.S.Ungerstedt,M.Blomback,T.Sodersterom,and et al.Nicotinamide is a potent inhibitor of proinflammatory cytokines.Clin Exp Immunol.2003.131:48-52.
70.Giorgia Cardinali,Simona Ceccarelli,Daniela Kovacs,and et al.Keratinocyte Growth Factor Promotes Melanosome Transfer to Keratinocytes.J Invest Dermatol.2005,125:1190-1199.
71.Mengeaud V,et al.Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in mudne melanoma cells.Pigment Cell Res,1994,7:245-254
72.Marwan MM,et al.Psoralens stimulate mouse melanocyte melanoma tyrosinase activity.In the absence of ultraviolet light.Pigment Cell Res,1990,3:214-221
73.雷铁池等。8-甲氧补骨脂素对小鼠黑素瘤细胞黑素生成的调节及相关信号转导研究。中华皮肤科杂志,1999,32(2):115-118。
74.马慧军等。甲氧沙林对培养人表皮黑素细胞黑素合成的影响及信号转导的研究。临床皮肤科杂志,2004,33(9):526-528。
75.吴晓慧,吴国荣,张卫明等.丹皮酚及其磺化物体外抗氧化作用.南京师大学报:自然科学版.2005,28(3):83-85.
76.唐景荣,石琳.丹皮酚对正常及钙反常培养乳鼠心肌细胞的抗氧化作用.中草药-1990,21(12):19-21.
77.陈江斌,唐其柱.丹皮酚抗心律失常的电生理机制.临床心电学杂志.1999:8(3):148-150.
78.张广钦,禹志领.丹皮酚对抗大鼠心肌缺血再灌注心律失常作为.中国药科大学学报.1997,28(4):225-227.
79.孙国平,沈玉先.丹皮酚的体内外抗肿瘤作用.安徽医科大学学报.2002:37(3):183-185.
80.巫冠中,杭秉茜.丹皮酚的抗变态反应作用.中国药科大学学报.1990,21(2):103-106.
81.R.Schmidt,P.Krien,M.Regnier,The use of diethylaminoethyl-cellulose membrane filters in a bioassay to quantify melanin synthesis,Anal.Biochem.235(1996) 113-118.
82.M.Regnier,C.Duval,J.B.Galey,M.Philippe,A.Lagrange,R.Tuloup,R.Schmidt,Keratinocyte-melanocyte co-cultures and pigmented reconstructed human epidermis:models to study modula-tion of melanogenesis,Cell.Mol.Biol.45(1999) 969-980.
83.W.Tur,A.G.Induchem,Tanning accelerators,Cosmet.Toilet.105(1990) 79-85.
84.A.Slominski,G.Moellmann,E.Kuklinska,and et al.Positive regulation of melanin pigmentation by two key substrates of the melanogenic pathway,L-tyrosine and L-dopa.J Cell Sci.89(1988) 287-296.
85.A Slominski,G Moellmann,E Kuklinska,and et al.L-Tyrosine,L-DOPA,and tyrosinase as positive regulators of the subcellular apparatus of melanogenesis in Bomirski Ab amelanotic melanoma cells,Pigment Cell Res.2(1989)109-116.
86.A.Slominski.L-Tyrosine induces synthesis of melanogenesis related melanoma proteins,Life Sci.45(1989) 1799-1803.
87.A Slominski,P Jastreboff,J Pawelek,L-Tyrosine stimulates induction of tyrosinase activity by MSH and reduces cooperative interactions between MSH receptors in hamster melanoma cells.Biosci.Rep.9(1989) 579-586.
88.A Slominski and Ralf Paus.Towards defining receptors for L-tyrosine and L-DOPA.Molecular and Cellular Endocrinology.1994,99:C7-C11.
89.王志均,陈孟勤主编。中国生理学史。北京:北京医科大学、中国协和医科大学联合出版社。
90.黄秉宪,潘华。控制理论在生物医学中的应用。生理科学进展。1979.10:54-62。
91.姚泰主编。生理学(第六版)。北京:人民卫生出版社,2004。
92.Slominski A,Moellomann G,and Kuklinska E.L-Tyrosine,L-DOPA,and tyrosinase as positive regulators of the subcellular apparatus of melanogenesis in bomiriski ab amelanotic melanoma cells.Pigmnet Cell Res.1989.2:109-116.
93.Poma A,Bianchini S,Miranda M.Inhibition of L-tyrosine-induced micronuclei production by phenylthiourea in human melanoma cells.Mutat Res.1999.446(2):143-8
94.徐丰彦,张镜如主编。人体生理学。北京:人民卫生出版社,1989。
95.赵辩主编。临床皮肤病学。南京:江苏科学技术出版社,2001。
Bentley, N.J., T. Eisen and C.R. Goding. Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. Mol. Cell. Biol. 14: 7996 8006,1994.
Bertolotto, C, P. Abbe, T.J. Hemesath, K. Bille, D.E. Fisher, J.P. Ortonne, and R. Ballotti. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.J. Cell Biol. 142: 827 835. 1998.
Choi, H., S. Ann, B.G. Lee, I. Chang and J.S. Hwang. Inhibition of skin pigmentation by an extract of Lepidium apetalum and its possible implication in IL-6 mediated signaling. Pigment Cell Res. 18: 439 446, 2005.
Friedmann, P.S., F.E. Wren and J.N. Mattews. Ultraviolet stimulated melanogenesis by human melanocytes is augmented by di-acyl glycerol but not TPA. J. Cell Physiol. 142: 334 341,1990.
Fuse, N., K. Yasumoto, H. Suzuki, K. Takahashi and S. Shibahara. Identification of a melanocyte-type promoter of the microphthalmia-associated transcription factor gene. Biochem. Biophys. Res. Commun. 219: 702 707,1996.
Galibert, D.M., S. Carreira and R.C. Goding. The Usf-1 transcription factor is a novel target for the stress-responsive p38 kinase and mediates UV-induced tyrosinase expression. EMBO J. 20: 5022 5031, 2001.
Goding, C.R. Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage. Genes. 14: 1712 1728, 2000.
Hata, K., K. Hori and S. Takahashi. Role of p38 MAPK in lupeol-induced B16 2F2 mouse melanoma cell differentiation. J. Biochem. 134: 441 445, 2003.
Hemesath, T.J., E.R. Price, C. Takemoto, T. Badalian and D.E. Fisher. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 391: 298 301,1998.
Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80: 225 236, 1995.
Kadekaro, A.L., R.J. Kavanagh, K. Wakamatsu, S. Ito, M.A. Pipitone and Z.A.
Abdel-Malek. Cutaneous photobiology. The melanocyte vs. the sun: who will win the final round? Pigment Cell Res. 16: 434 447, 2003.
Kim, D.S., E.S. Hwang, J.E. Lee, S.Y. Kim, S.B. Kwon and K.C. Park. Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation. J. Cell Sci. 116: 1699 1706, 2003.
Kim, D.S., S.H. Park, S.B. Kwon, E.S. Park, C.H. Huh, S.W. Youn and K.C. Park. Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes. Pigment Cell Res. 19: 146 153, 2005.
Kim, D.S. A new 2-imino-l,3-thiazoline derivative, KHG22394, inhibits melanin synthesis in mouse B16 melanoma cells. Biol. Pharm. Bull. 30(1): 180 183, 2007.
Mansky, K.C., U. Sankar, J. Han and M.C. Ostrowski. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. J. Biol. Chem. 277: 11077 11083, 2002.
Mun, Y.J., S.W. Lee, H.W. Jeong, K.G. Lee, J.H. Kim and W.H. Woo. Inhibitory effect of miconzole on melanogensis. Biol. Pharm. Bull. 6: 806 809, 2004.
Price E.R., M. A. Horstmann, A.G. Wells, K.N. Weilbaecher, C.M. Takemoto, M. W. Landis and D.E. Fisher. a-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg Syndrome. J. Biol. Chem. 273(49): 33042 33047, 1998 Saha, B., S.K. Singh, C. Sarkar, R. Bera, J. Ratha, D.J. Tobin and R. Bhadra. Activation of the Mitf promoter by lipid-stimulated activation of p38-stress signalling to CREB. Pigment Cell Res. 19: 595 605, 2006.
Smalley, K. and T. Eisen. The involvement of p38 mitogenactivated protein kinase in the a-melanocyte stimulating hormone (aMSH)-induced melanogenic and anti-proliferative effects in B16 melanoma cells. FEBS Lett. 476: 198 202, 2000.
Sugimoto, K., T. Nishimura and K. Nomura. Inhibitory effects of alpha-arbutin on melanin synthesis in cultured human cells and three-dimensional human skin model. Biol. Pharm. Bull. 4: 510 514, 2004.
Tachibana, M. MITF: a stream flowing for pigment cells. Pigment Cell Res. 13: 230 240,2000.
Tada, A., E. Pereira, D. Beitner-Johnson, R. Kavanagh and Z.A. Abdel-Malek. Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. J. Invest. Dermatol. 118: 316 322, 2002.
Wu, M., T.J. Hemesath, C.M. Takemoto, M.A. Horstmann, A.G. Wells, E.R. Price, D.Z. Fisher and D.E. Fisher. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes 14: 301 312, 2000.
Xie, S.H., Z.Q. Chen and P.C. Ma. Down-regulation of melanin synthesis and transfer by paeonol and its mechanisms. Am. J. Chin. Med. 35(1): 141 153, 2007.
Yasumoto, K., K. Yokoyama, K. Shibata, Y. Tomita and S. Shibahara. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol. Cell. Biol. 14: 8058 8070,1994.
1.Passeron T,Bahadoran P,Bertolotto C,et al.Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association[J].The FASEB Journa,2004,18(9):989-91.
2.Duarte C.Barral and Miguel C.Seabra.The Melanosome as a Model to Study Organelle Motility in Mammals[J].Pigment Cell Res.2004,17:111-118.
3.Deacon SW,Serpinskaya AS,Vaughan PS,et al.Dynactin is Required for Bidirectional Organelle Transport[J].The Journal of Cell Biology,2003,160(3):297-301.
4.Hume AN,Collinson LM,Rapak A,et al.Rab27a Regulates the Peripheral Distribution of Melanosomes in Melanocytes[J].The Journal of Cell Biology,2001,152(4):795-808.
5.Englaro W,Rezzonico R,Durand-Clement M,et al.Mitogen activated Protein Kinase Pathway and AP-1 Are Activated during camp-induced Melanogenesis in B-16 Melanoma Cell[J].The Journal of Biological Chemistry.1995,270(41):24315-24320.
6.Reilein AR,Tint IS,Peunova NI,et al.Regulation of Organelle Movement in Melanophores by Protein Kinase A(PKA),Protein Kinase C(PKC),and Protein Phosphatase 2A[J]. The Journal of Cell Biology, 1998,142(3): 803-813.
7. Skold HN, Norstrom E, Wallin M. Regulation Control of Both Microtubule-and Actin-dependent Fish Melanosome Movement[J]. Pigment Cell Res, 2002, 15: 357-366.
8. Aspengren S, Skold HN, Quiroga G, et al. Noradrenaline- and Melantin-Mediated Regulation of Pigment Aggregation in Fish Melanophore[J]. Pigment Cell Res, 2003,16: 59-64.
9. Deacon SW, Nascimento A, Serpinskaya AS, et al. Regulation of Bidirectional Melanosome Transport by Organelle Bound MAP Kinase[J]. Current Biology, 2005, 15: 459-463.
10. Andersson TP, Svensson SP, Karlsson AM. Regulation of Melanosome Movement by MAP Kinase[J]. Pigment Cell Res, 2003, 15: 215-221.
11. Cook SJ, McCormick F .Inhibition by cAMP of Ras-dependent activation of Raf[J]. Science 1993, 262(5136): 1069-72
12. David Sugden and Sally J. Rowe. Protein Kinase C Activation Antagonizes Melatonin-induced Pigment Aggregation in Xenopus laevis Melanophores[J]. The Journal of Cell Biology, 1992,119,(6) :1515-1521.
13. Nilsson HM, Karlsson AM, Loitto VM, et al. Nitric Oxide Modulates Intracellular Translocation of Pigment Organelles in Xenopus Laevis. Cell Motil[J]. Cytoskeleton. 2000,47(3):209-18.
14. Nilsson HM,Svensson SP, Sundqvist T. .L-NAME-induced Dispersion of Melanosomes in melanophore activates PKC, MEK and ERK1[J]. Pigment Cell Res, 2001, 14(6): 450-5.
15. Oudit GY, Sun H, Kerfant BG, et al. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease[J]. J Mol Cell Cardiol .2004 ,37(2):449-71
16. Andersson TP, Skold HN,Svensson SP. Phosphoinositide 3-kinase is Involved in Xenopus and Labrus melanophore aggregation[J].Cell Signal, 2003,15(12): 1119-1127.
2.Xie Sh,Chen ZQ,and Ma PC.Down-regulation of melanin synthesis and transfer by paeonol and its mechanisms[J].The American Journal of Chinese Medicine(AJCM).2007,35(1):141-153.
3.解士海,陈志强,马鹏程,卜今等.人表皮黑素细胞与角质形成细胞共培养体外模型中黑素小体转运的观察.临床皮肤科杂志.2006;35(5):286-288.
4.Hara M,Yaar M,Gilchrest BA.Endothelinol of keratinocyte origin is a mediator of melanocyte dendricity.J Invest Dermatol.1995.105(6):744-8.
5.Luo D,Chen H,Searles G,et al.Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanin pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R.Melanoma Res.1995.5(5):303-9.
6.Brenner M,Degitz K,Besch R and Berking C.Differential expression of melanoma-associated growth factors in keratinocytes and fibroblasts by ultraviolet A and ultraviolet B radiation.British J Dermatol.2005.153:733-739.
7.Akira Hachiya,Akemi Kobayashi,Yasuko Yoshida,and et al.Biphasic Expression of Two Paracrine Melanogenic Cytokines,Stem Cell Factor and Endothelin-1,in Ultraviolet B-Induced Human Melanogenesis.American Journal of Pathology.2004.165(6):2099-2109.
8.Tada A,Sukuki I,Im S,et al.Endotherlin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation.Cell Growth Differentiation.1998,9:575-584
9.傅国强,马鹏程等.196味中药乙醇提取物对酪氨酸酶的抑制作用。中华皮肤科杂志,2003,2(36):103-106
10.Xie SH,Chen ZQ,and Ma PC.Down-regulation of melanin synthesis and transfer by paeonol and its mechanisms [J]. The American Journal of Chinese Medicin e (AJCM). 2007,35(1): 141-153.
11. Kageyama A, Oka M, Okada T. Down-regulation of melanogenesis by phospholipase D2 through ubiquitin proteasome-mediated degradation of tyrosinase[J]. J. Biol. Chem. 2004,279(26): 27774-27780.
12. Kim DS, Jeong YM, Park IK, et al. Anew 2-Imino-l,3-thiazoline derivative, KHG22394, inhibits melanin synthesis in mouse B16F10 melanoma cells[J]. Biol. Pharm. Bull. 2007,30(1): 180-183.
13. Lin CB, Babiarz L, Liebel F, et al. Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation [J]. J Invest Dermatol. 2002,119(6): 1330-40.
14. Vance K and Goding CR. The transcription network regulating melanocyte development and melanoma[J]. Pigment Cell Res. 2004,17:318-325.
15. Widlund HR and Fisher DE. Microphthalmia-associated transcription factor: a critical regulator of pigment cell development and survival [J]. Oncogene. 2003,22:3035-3041.
16. Tachibana M. Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A[J]. Pigment Cell Res. 1997,10: 25-33.
17. Fuse, N., K. Yasumoto, H. Suzuki, et al. Identification of a melanocyte-type promoter of the microphthalmia-associated transcription factor gene. Biochem. Biophys. Res. Commun. 1996.219: 702 707.
18. Land EJ and Riley PA. Spontaneous redox reactions of dopaquinone and the balance between the eumelanic and phaeomelanic pathways [J]. Pigment Cell Research.2000,13(4): 273-277.
19. Price ER, Horstmann MA, Wells AG, et al. Alpha-melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg Syndrome[J]. J Biol Chem. 1998,273(49): 33042-33047.
20. Bertolotto, C, P. Abbe, T.J. Hemesath, K. et al. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.J.Cell Biol.1998.142:827 835.
21.Hemesath,T.J.,E.R.Price,C.Takemoto,T.et al.MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes.Nature1998.391:298 - 301
22.Wu,M.,T.J.Hemesath,C.M.Takemoto,M.A.et al.c-Kit triggers dual phosphorylations,which couple activation and degradation of the essential melanocyte factor Mi.Genes 14:301 - 312,2000.
23.陈晓宇,陈明,李俊.MAPKs信号转导在类风湿性关节炎滑膜细胞中作用.中国药理学通报,2006 12:1424-1428.
24.廖清船,肖洲生,秦艳芳,刘亭,等.植物雌激素金雀异黄酮通过p38MAP通路促进骨髓间充质干细胞向成骨细胞分化.中国药理学通报,2006,06:683-687.
25.袁辉,杨胜,周文霞,等.MAPK级联信号通路与长时程增强[J].中国药理学通报,2006,22(7):769-74.
26.Kim,D.S.,S.H.Park,S.B.Kwon,E.S.Park,C.H.Huh,S.W.Youn and K.C.Park.Sphingosylphosph orylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes.Pigment Cell Res.19:146 - 153,2005.
27.Choi,H.,S.Ahn,B.G.Lee,I.Chang and J.S.Hwang.Inhibition of skin pigmentation by an extract of Lepidium apetalum and its possible implication in IL-6 mediated signaling.Pigment Cell Res.18:439 - 446,2005.
28.Kim,D.S.A new 2-imino-l,3-thiazoline derivative,KHG22394,inhibits melanin synthesis in mouse B16 melanoma cells.Biol.Pharm.Bull,30(1):180-183,2007.
29.Saha,B.,S.K.Singh,C.Sarkar,R.Bera,J.Ratha,D.J.Tobin and R.Bhadra.Activation of the Mitf promoter by lipid-stimulated activation of p38-stress signalling to CREB.Pigment Cell Res.19:595 - 605,2006.
30.Tada,A.,E.Pereira,D.Beitner-Johnson,R.Kavanagh and Z.A.Abdel-Malek.Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes.J.Invest.Dermatol.118:316 - 322,2002.
31.Smalley,K.and T.Eisen.The involvement of p38 mitogenactivated protein kinase in the a-melanocyte stimulating hormone(aMSH)-induced melanogenic and anti-proliferative effects in B16 melanoma cells.FEBS Lett.476:198 - 202,2000.
32.Mansky,K.C.,U.Sankar,J.Han and M.C.Ostrowski.Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling.J.Biol.Chem.277:11077-11083,2002.
33.Mengeaud V and Ortonne JP.Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in murine melanoma cells.Pigment Cell Res.1994.7:245-254.
34.雷铁池,朱文远。与表皮黑素细胞增殖和黑素生成相关的信号转导。国外医学皮肤性病学分册。1999,25(1):32-35.
35.Yoon H S,Lee S R,Ko H C,et al.Involvement of extracellular signal-regulated kinase in nobiletin-induced melanogenesis in murine B16/F10 melanoma cells.Biosci Biotechnol Biochem,2007,71(7):1781-4.
36.Park S H,Kim D S,Kim W G,et al.Terrein:a new melanogenesis inhibitor and its mechanism.Cell Mol Life Sci,2004,61(22):2878-85.
37.Kim D S,Park S H,Kwon S B,et al.Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes[J].Pigment Cell Res,2005,19:146-53.
38.Hirata N,Naruto S,Ohguchi K,et al.Mechanism of the melanogenesis stimulation activity of(-)-cubebin in murine B16 melanoma cells[J].Bioorg Med Chem,2007,15(14):4897-902.
39.Yanagisawa M,Kurihara H,Kimura S,and et al.A novel peptide vasoconstrictor,endothelin,is produced by vascular endothelium and modulates smooth muscle Ca2_ channels.Nature 1988,322:411-415.
40.Inoue A,Yanagisawa M,Kimura S,et al.The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. Proc Natl Acad Sci USA .1989, 86:2863-2867.
41. M. Okazaki, K. Yoshimura, G. Uchida and K. HariiCorrelation between age and the secretions of melanocyte-stimulating cytokines in cultured keratinocytes and fibroblasts. British J of Dermatol. 2005. 153(suppl 2): 23-29.
42. Akira Hachiya, Akemi Kobayashi, Yasuko Yoshida, and et al. Biphasic Expression of Two Paracrine Melanogenic Cytokines, Stem Cell Factor and Endothelin-1, in Ultraviolet B-Induced Human Melanogenesis. American Journal of Pathology. 2004.165(6): 2099-2109.
43. Kadono S, Manaka Izumi, Kawashima M, and et al. The role of the epidermal endothelin cascade in the hyperpigmnetation mechanism of Lentigo Senilis. J Invest Dermatol. 2001.116(4): 571-577.
44. Kunisada T, Lu SZ, Yoshida H, and et al. Murine cutaneous mastocytosis and epidermal melanocytosis induced by kerationcyte expression of transgenic stem cell factor. J Exp Med. 1998.187(10): 1565-1573.
45. Giebel LB, Spritz RA.. Mutation of the KIT (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. Proc Natl Acad Sci USA 1991. 88:8696-8699.
46. Fleischman RA, Saltman DL, Stastny V, Zneimer S.. Deletion of the c-kit protooncogene in the human developmental defect piebald trait. Proc Natl Acad Sci USA. 1991.88:10885-10889.
47. Lee AY, Kim AH, Choi WI, and Youm YH. Less keratinocyte-derived factor related to more keratinocyte apoptosis in depigmented than normally pigmented suction-blistered epidermis may cause passive melanocyte death in vitiligo. J Invest Dermatol. 2005. 124976-983.
48. Moretti S, Spallanzani A, Amato L, and et al. New insights into the pathogenesis of vitiligo: Imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res. 2002. 15:87-92.
49. Grabbe J, Welker P, Rosenbach T, et al: Release of stem cell factor from a human keratinocyte line, HaCaT, is increased in differentiating versus proliferating cells. J Invest Dermatol. 1996.107:219-224.
50. Hachiya A, Kobayashi A, Ohuchi A, Takema Y, Imokawa G: The paracrine roleof stem cell factor/c-kit signaling in the activation of human melanocytes in ultraviolet-B-induced pigmentation. J Invest Dermatol. 2001. 116:578-586.
51. Kunisada T, Lu SZ, Yoshida H, et al: Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J Exp Med. 1998.187:1565-1573.
52. Genji Imokawa. Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res. 2004. 17:96-110.
53. Welker P, Grabbe J, Gibbs B, Zuberbier T, Henz BM: Human mast cells produce and differentially express both soluble and membrane-bound stem cell factor. Scand J Immunol. 1999.49:495-500.
54. Jurgen Grabbe, Pia Welker, Thomas Rosenbach, et al. Release of Stem Cell Factor from a Human Keratinocyte Line, HaCat, Is Increased in Differentiating versus Proliferating Cells. The Journal of Investigative Dermatology. 1996, 107(2): 219-224.
55. Hidehiko Baba, Hideyo Uchiwa and Shinichi Watanabe. UVB Irradiation Increases the Release of SCF from Human Epidermal Cells.The Journal of Investigative Dermatology. 2004,124(5): 1075-1077.
56. Kadono S, Manaka I, Kawashima M, at al. The role of the epidermal endothelin cascade in the hyperpigmentation mechanism of Lentigo Senilis. J Invest Dermatol. 2001,116:571-577.
57. Palumbo A, d'Ischia M, Misuraca G, Prota G. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. 1991 23;1073(1):85-90.
58.Smith CI,et al. Selective cytotoxicity of hydroquinone for melanocyte-derived cells is mediated by tyrosinase activity but independent of melanin content. Pigment Cell Res, 1988,1(6): 386-9.
59.王大光等。淫羊藿苷抑制正常黑素细胞黑素合成的研究。临床皮肤科杂志,2004,33(8):460-462。
60.Chakraborty AK,Funasaka Y,Komoto M,Ichihashi M.Effect of arbutin on melanogenic proteins in human melanocytes.Pigrnent Cell Res.1998,11(4):206-12.
61.丁国斌陈璧等.熊果苷对体外培养的人黑素细胞的作用.第四军医大学学.2001.22(20):1846-1848.
62.SUGIMOTO,Takahisa NISHIMURA,Koji NOMURA,and et al.Inhibitory Effects of a-Arbutin on Melanin Synthesis in Cultured Human Melanoma Cells and a Three-Dimensional Human Skin Model Kazuhisa Biol.Pharm.Bull.27(4)510-514(2004)
63.解士海。人表皮黑素细胞-角质形成细胞共培养及11种化合物对黑素沉着的影响研究。中国协和医科大学,中国医学科学院博士研究生论文。2006。
64.Kamat JP,Devasagayam TP.Nicotinamide(vitamin B3) as an effective antioxidant against oxidative damage in rat brain mitochondria.Redox Rep.1999,4(4):179-84.
65.Chen CF,Wang D,Hwang CP,Liu HW.The protective effect of niacinamide on ischemia-reperfusion-induced liver injury.J Biomed Sci.2001Nov-Dec;8(6):446-52.
66.Hakozaki T et al.The Effect of Niacinamide On Reducing Cutaneous Pigmentation and Suppression of Melanosome Transfer.British J Dermatol,2002,147:20-31.
67.Lei TC,Virador VM,Vieira WD,et al.A melanocyte-keratinocyte co-culture model to assess regulators of pigmentation in vitro.Analytical Biochemistry,2002,305:260-268.
68.Yang SX,Mortari AP,Shukla M,et al.Exuberant Inflammation in Nicotinamide Adenine Dinucleotide Phosphate-Oxidase-Deficient Mice After Allogeneic Marrow Transplantation.The Journal of Immunology.2002,168:5840-5847.
69.J.S.Ungerstedt,M.Blomback,T.Sodersterom,and et al.Nicotinamide is a potent inhibitor of proinflammatory cytokines.Clin Exp Immunol.2003.131:48-52.
70.Giorgia Cardinali,Simona Ceccarelli,Daniela Kovacs,and et al.Keratinocyte Growth Factor Promotes Melanosome Transfer to Keratinocytes.J Invest Dermatol.2005,125:1190-1199.
71.Mengeaud V,et al.Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in mudne melanoma cells.Pigment Cell Res,1994,7:245-254
72.Marwan MM,et al.Psoralens stimulate mouse melanocyte melanoma tyrosinase activity.In the absence of ultraviolet light.Pigment Cell Res,1990,3:214-221
73.雷铁池等。8-甲氧补骨脂素对小鼠黑素瘤细胞黑素生成的调节及相关信号转导研究。中华皮肤科杂志,1999,32(2):115-118。
74.马慧军等。甲氧沙林对培养人表皮黑素细胞黑素合成的影响及信号转导的研究。临床皮肤科杂志,2004,33(9):526-528。
75.吴晓慧,吴国荣,张卫明等.丹皮酚及其磺化物体外抗氧化作用.南京师大学报:自然科学版.2005,28(3):83-85.
76.唐景荣,石琳.丹皮酚对正常及钙反常培养乳鼠心肌细胞的抗氧化作用.中草药-1990,21(12):19-21.
77.陈江斌,唐其柱.丹皮酚抗心律失常的电生理机制.临床心电学杂志.1999:8(3):148-150.
78.张广钦,禹志领.丹皮酚对抗大鼠心肌缺血再灌注心律失常作为.中国药科大学学报.1997,28(4):225-227.
79.孙国平,沈玉先.丹皮酚的体内外抗肿瘤作用.安徽医科大学学报.2002:37(3):183-185.
80.巫冠中,杭秉茜.丹皮酚的抗变态反应作用.中国药科大学学报.1990,21(2):103-106.
81.R.Schmidt,P.Krien,M.Regnier,The use of diethylaminoethyl-cellulose membrane filters in a bioassay to quantify melanin synthesis,Anal.Biochem.235(1996) 113-118.
82.M.Regnier,C.Duval,J.B.Galey,M.Philippe,A.Lagrange,R.Tuloup,R.Schmidt,Keratinocyte-melanocyte co-cultures and pigmented reconstructed human epidermis:models to study modula-tion of melanogenesis,Cell.Mol.Biol.45(1999) 969-980.
83.W.Tur,A.G.Induchem,Tanning accelerators,Cosmet.Toilet.105(1990) 79-85.
84.A.Slominski,G.Moellmann,E.Kuklinska,and et al.Positive regulation of melanin pigmentation by two key substrates of the melanogenic pathway,L-tyrosine and L-dopa.J Cell Sci.89(1988) 287-296.
85.A Slominski,G Moellmann,E Kuklinska,and et al.L-Tyrosine,L-DOPA,and tyrosinase as positive regulators of the subcellular apparatus of melanogenesis in Bomirski Ab amelanotic melanoma cells,Pigment Cell Res.2(1989)109-116.
86.A.Slominski.L-Tyrosine induces synthesis of melanogenesis related melanoma proteins,Life Sci.45(1989) 1799-1803.
87.A Slominski,P Jastreboff,J Pawelek,L-Tyrosine stimulates induction of tyrosinase activity by MSH and reduces cooperative interactions between MSH receptors in hamster melanoma cells.Biosci.Rep.9(1989) 579-586.
88.A Slominski and Ralf Paus.Towards defining receptors for L-tyrosine and L-DOPA.Molecular and Cellular Endocrinology.1994,99:C7-C11.
89.王志均,陈孟勤主编。中国生理学史。北京:北京医科大学、中国协和医科大学联合出版社。
90.黄秉宪,潘华。控制理论在生物医学中的应用。生理科学进展。1979.10:54-62。
91.姚泰主编。生理学(第六版)。北京:人民卫生出版社,2004。
92.Slominski A,Moellomann G,and Kuklinska E.L-Tyrosine,L-DOPA,and tyrosinase as positive regulators of the subcellular apparatus of melanogenesis in bomiriski ab amelanotic melanoma cells.Pigmnet Cell Res.1989.2:109-116.
93.Poma A,Bianchini S,Miranda M.Inhibition of L-tyrosine-induced micronuclei production by phenylthiourea in human melanoma cells.Mutat Res.1999.446(2):143-8
94.徐丰彦,张镜如主编。人体生理学。北京:人民卫生出版社,1989。
95.赵辩主编。临床皮肤病学。南京:江苏科学技术出版社,2001。
Bentley, N.J., T. Eisen and C.R. Goding. Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. Mol. Cell. Biol. 14: 7996 8006,1994.
Bertolotto, C, P. Abbe, T.J. Hemesath, K. Bille, D.E. Fisher, J.P. Ortonne, and R. Ballotti. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.J. Cell Biol. 142: 827 835. 1998.
Choi, H., S. Ann, B.G. Lee, I. Chang and J.S. Hwang. Inhibition of skin pigmentation by an extract of Lepidium apetalum and its possible implication in IL-6 mediated signaling. Pigment Cell Res. 18: 439 446, 2005.
Friedmann, P.S., F.E. Wren and J.N. Mattews. Ultraviolet stimulated melanogenesis by human melanocytes is augmented by di-acyl glycerol but not TPA. J. Cell Physiol. 142: 334 341,1990.
Fuse, N., K. Yasumoto, H. Suzuki, K. Takahashi and S. Shibahara. Identification of a melanocyte-type promoter of the microphthalmia-associated transcription factor gene. Biochem. Biophys. Res. Commun. 219: 702 707,1996.
Galibert, D.M., S. Carreira and R.C. Goding. The Usf-1 transcription factor is a novel target for the stress-responsive p38 kinase and mediates UV-induced tyrosinase expression. EMBO J. 20: 5022 5031, 2001.
Goding, C.R. Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage. Genes. 14: 1712 1728, 2000.
Hata, K., K. Hori and S. Takahashi. Role of p38 MAPK in lupeol-induced B16 2F2 mouse melanoma cell differentiation. J. Biochem. 134: 441 445, 2003.
Hemesath, T.J., E.R. Price, C. Takemoto, T. Badalian and D.E. Fisher. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 391: 298 301,1998.
Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80: 225 236, 1995.
Kadekaro, A.L., R.J. Kavanagh, K. Wakamatsu, S. Ito, M.A. Pipitone and Z.A.
Abdel-Malek. Cutaneous photobiology. The melanocyte vs. the sun: who will win the final round? Pigment Cell Res. 16: 434 447, 2003.
Kim, D.S., E.S. Hwang, J.E. Lee, S.Y. Kim, S.B. Kwon and K.C. Park. Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation. J. Cell Sci. 116: 1699 1706, 2003.
Kim, D.S., S.H. Park, S.B. Kwon, E.S. Park, C.H. Huh, S.W. Youn and K.C. Park. Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes. Pigment Cell Res. 19: 146 153, 2005.
Kim, D.S. A new 2-imino-l,3-thiazoline derivative, KHG22394, inhibits melanin synthesis in mouse B16 melanoma cells. Biol. Pharm. Bull. 30(1): 180 183, 2007.
Mansky, K.C., U. Sankar, J. Han and M.C. Ostrowski. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. J. Biol. Chem. 277: 11077 11083, 2002.
Mun, Y.J., S.W. Lee, H.W. Jeong, K.G. Lee, J.H. Kim and W.H. Woo. Inhibitory effect of miconzole on melanogensis. Biol. Pharm. Bull. 6: 806 809, 2004.
Price E.R., M. A. Horstmann, A.G. Wells, K.N. Weilbaecher, C.M. Takemoto, M. W. Landis and D.E. Fisher. a-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg Syndrome. J. Biol. Chem. 273(49): 33042 33047, 1998 Saha, B., S.K. Singh, C. Sarkar, R. Bera, J. Ratha, D.J. Tobin and R. Bhadra. Activation of the Mitf promoter by lipid-stimulated activation of p38-stress signalling to CREB. Pigment Cell Res. 19: 595 605, 2006.
Smalley, K. and T. Eisen. The involvement of p38 mitogenactivated protein kinase in the a-melanocyte stimulating hormone (aMSH)-induced melanogenic and anti-proliferative effects in B16 melanoma cells. FEBS Lett. 476: 198 202, 2000.
Sugimoto, K., T. Nishimura and K. Nomura. Inhibitory effects of alpha-arbutin on melanin synthesis in cultured human cells and three-dimensional human skin model. Biol. Pharm. Bull. 4: 510 514, 2004.
Tachibana, M. MITF: a stream flowing for pigment cells. Pigment Cell Res. 13: 230 240,2000.
Tada, A., E. Pereira, D. Beitner-Johnson, R. Kavanagh and Z.A. Abdel-Malek. Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. J. Invest. Dermatol. 118: 316 322, 2002.
Wu, M., T.J. Hemesath, C.M. Takemoto, M.A. Horstmann, A.G. Wells, E.R. Price, D.Z. Fisher and D.E. Fisher. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes 14: 301 312, 2000.
Xie, S.H., Z.Q. Chen and P.C. Ma. Down-regulation of melanin synthesis and transfer by paeonol and its mechanisms. Am. J. Chin. Med. 35(1): 141 153, 2007.
Yasumoto, K., K. Yokoyama, K. Shibata, Y. Tomita and S. Shibahara. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol. Cell. Biol. 14: 8058 8070,1994.
1.Passeron T,Bahadoran P,Bertolotto C,et al.Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association[J].The FASEB Journa,2004,18(9):989-91.
2.Duarte C.Barral and Miguel C.Seabra.The Melanosome as a Model to Study Organelle Motility in Mammals[J].Pigment Cell Res.2004,17:111-118.
3.Deacon SW,Serpinskaya AS,Vaughan PS,et al.Dynactin is Required for Bidirectional Organelle Transport[J].The Journal of Cell Biology,2003,160(3):297-301.
4.Hume AN,Collinson LM,Rapak A,et al.Rab27a Regulates the Peripheral Distribution of Melanosomes in Melanocytes[J].The Journal of Cell Biology,2001,152(4):795-808.
5.Englaro W,Rezzonico R,Durand-Clement M,et al.Mitogen activated Protein Kinase Pathway and AP-1 Are Activated during camp-induced Melanogenesis in B-16 Melanoma Cell[J].The Journal of Biological Chemistry.1995,270(41):24315-24320.
6.Reilein AR,Tint IS,Peunova NI,et al.Regulation of Organelle Movement in Melanophores by Protein Kinase A(PKA),Protein Kinase C(PKC),and Protein Phosphatase 2A[J]. The Journal of Cell Biology, 1998,142(3): 803-813.
7. Skold HN, Norstrom E, Wallin M. Regulation Control of Both Microtubule-and Actin-dependent Fish Melanosome Movement[J]. Pigment Cell Res, 2002, 15: 357-366.
8. Aspengren S, Skold HN, Quiroga G, et al. Noradrenaline- and Melantin-Mediated Regulation of Pigment Aggregation in Fish Melanophore[J]. Pigment Cell Res, 2003,16: 59-64.
9. Deacon SW, Nascimento A, Serpinskaya AS, et al. Regulation of Bidirectional Melanosome Transport by Organelle Bound MAP Kinase[J]. Current Biology, 2005, 15: 459-463.
10. Andersson TP, Svensson SP, Karlsson AM. Regulation of Melanosome Movement by MAP Kinase[J]. Pigment Cell Res, 2003, 15: 215-221.
11. Cook SJ, McCormick F .Inhibition by cAMP of Ras-dependent activation of Raf[J]. Science 1993, 262(5136): 1069-72
12. David Sugden and Sally J. Rowe. Protein Kinase C Activation Antagonizes Melatonin-induced Pigment Aggregation in Xenopus laevis Melanophores[J]. The Journal of Cell Biology, 1992,119,(6) :1515-1521.
13. Nilsson HM, Karlsson AM, Loitto VM, et al. Nitric Oxide Modulates Intracellular Translocation of Pigment Organelles in Xenopus Laevis. Cell Motil[J]. Cytoskeleton. 2000,47(3):209-18.
14. Nilsson HM,Svensson SP, Sundqvist T. .L-NAME-induced Dispersion of Melanosomes in melanophore activates PKC, MEK and ERK1[J]. Pigment Cell Res, 2001, 14(6): 450-5.
15. Oudit GY, Sun H, Kerfant BG, et al. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease[J]. J Mol Cell Cardiol .2004 ,37(2):449-71
16. Andersson TP, Skold HN,Svensson SP. Phosphoinositide 3-kinase is Involved in Xenopus and Labrus melanophore aggregation[J].Cell Signal, 2003,15(12): 1119-1127.