白色念珠菌CaBEM1,CaSRB9,CZF2及CaFLO11基因的克隆和功能研究
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摘要
白色念珠菌是一种重要的人体致病真菌，致病机制与其形态发生紧密相关。
白色念珠菌在不同的生长条件下能发生显著的形态变化，这种变化由多种调控
因子与信号转导途径所调控。酿酒酵母的G1 期细胞周期蛋白Cln1 和Cln2 参与
了其形态发生，cln1/cln1 cln2/cln2 双缺失株不能形成菌丝。把白色念珠菌基因组
文库导入cln1/cln1 cln2/cln2 缺失株，筛选能校正菌丝形成缺陷的基因，分离得
到白色念珠菌中的CaBEM1 基因。从核苷酸序列推导，CaBEM1 编码一个632
个氨基酸的蛋白，氨基酸序列分析表明在其N 端有两个SH3 结构域，中部有一
个PX结构域，C端有一个PB1结构域；CaBEM1的氨基酸序列与酿酒酵母的Bem1
同源性达38%， 与裂殖酵母的Scd2同源性达32％。 在酿酒酵母的缺失株中异源
表达CaBEM1， 能够部分校正它们在氮源缺乏条件下的菌丝形成缺陷。这种菌
丝形成的校正作用绕过MAPK途径和cAMP/PKA途径，表明CaBem1在菌丝形
成中的作用可能位于这两条信号传导途径的下游。
酿酒酵母Flo8 因子在其形态发生中起重要作用，我们把白色念珠菌基因组
DNA导入酿酒酵母flo8基因缺失株中，筛选能够互补flo8侵入生长缺陷的基因，
分离到了14个新基因，包括CaSRB9， CZF2和CaFLO11等基因。
CaSRB9 基因编码区全长4998 bp， 编码一个1665 个氨基酸的蛋白质。该基
因产物与酿酒酵母SRB9基因编码的产物具有最高的同源性，因此命名为CaSRB9
（C. albicans SRB9）。 在双倍体酿酒酵母中异源表达CaSRB9可以部分校正MAPK
途径基因缺失株以及flo8 缺失株的菌丝生长缺陷；在单倍体酿酒酵母中表达能
够互补flo8 缺失株的侵入生长缺陷，但在MAPK 途径基因缺失株中不能形成侵
入生长。
CZF2 Candida albicans zinc finger protein 基因的编码区为1875bp ，由序列
推断编码一种624个氨基酸的蛋白Czf2， 属于GAL4真菌转录调控蛋白家族。Czf2
的N端有一个保守的Zn2Cys6锌指结构域，这一结构域中有六个半胱氨酸残基，
结合两个锌离子形成结合DNA 的锌簇（zinc cluster）。 在双倍体酿酒酵母中异
源表达CZF2 可以部分校正MAPK 途径基因缺失株以及flo8 缺失株的菌丝生长
缺陷；在单倍体酿酒酵母中异源表达Czf2能够校正MAPK途径基因缺失株以及
flo8缺失株的侵入生长缺陷。用同源重组法敲除了白色念珠菌CZF2基因。czf2/czf2
缺失株在一些固体培养基中有轻微的菌丝形成缺陷。在YPD 中培养时形成伸长
的细胞。表明CZF2 基因的缺失对其形态发生有一定影响。以小鼠系统感染模型
研究发现，czf2/czf2缺失株的毒性比野生型略有下降。
CaFLO11 （C. albicans FLO11） 基因编码区为1962bp， 由序列推断编码一个
653 个氨基酸的蛋白质。从氨基酸序列分析预测CaFlo11 是一个细胞壁蛋白，其
N端有信号肽序列，C末端具有GPI结构域，中部含有多个由丝氨酸和苏氨酸组
成的串联重复序列。在双倍体酿酒酵母中异源表达CaFLO11 可以强烈地激活菌
丝生长，这种激活绕过MAPK 途径以及cAMP/PKA 途径。在单倍体酿酒酵母中
表达能够使MAPK 途径基因缺失株以及flo8 缺失株形成很强的侵入生长。用同
源重组法敲除白色念珠菌CaFLO11 基因，caflo11/caflo11 缺失株没有明显的菌丝
形成缺陷，但在某些液体培养基中形成的菌丝较为粗短。以小鼠系统感染模型
研究发现，CaFLO11的缺失对白色念珠菌的毒性几乎没有影响。
酿酒酵母MAPK 途径成员缺失株biofilm 形成能力降低。外源表达CZF2 和
CaFLO11 能不同程度地校正这些缺失株的biofilm 形成缺陷，但不能校正flo8 缺
失株的biofilm 形成缺陷。CaFLO11 能轻微地校正flo11 缺失株的biofilm 形成缺
陷。
Candida albicans is the most frequently isolated fungal pathogen in humans. The
pathogenic fungus Candida albicans has a dimorphic transition in various environmental
conditions. Many regulatory factors and several transduction pathways have been
identified in controlling filamentous growth. G1 cyclins Cln1 and Cln2 have been reported
as involved in the control of morphogenesis in Saccharomyces cerevisiae. Diploid
cln1/cln1 cln2/cln2 strains completely lost the ability to form pseudohyphae. A C.
albicans genomic DNA library was introduced into cln1/cln1 cln2/cln2 mutant to screen
genes which could complement its filamentous growth defect. In this screening, a BEM1
homolog, CaBEM1, was identified. The CaBEM1 gene has an ORF of 1899 bp, encoding
a putative protein of 632 amino acids. The CaBem1 protein shares highest homology in
amino acids with Bem1(38%) of S. cerevisiae and Scd2(32%) of Schizosaccharomyces
pombe. Sequence analysis showed that the CaBem1 contains two N-terminal SH3
domains, a PX domain and a C-terminal PB1 domain. It is believed these domains are
required for binding to proteins involved in polarized growth in S. cerevisiae and S. pombe.
Ectopic expression of the CaBEM1 gene in diploid S. cerevisiae suppressed defects in
filamentous growth of some mutants under nitrogen starvation conditions. This
suppression bypassed MAPK pathway and cAMP/PKA pathway in filamentous growth.
These results suggest that the CaBem1 protein may be a downstream component of these
two signal transduction pathways for filaments formation.
Flo8 plays an important role in morphogenesis of Saccharomyces cerevisiae. In this
work, a C. albicans genomic DNA library was introduced into an S. cerevisiae flo8/flo8
mutant to screen genes which could complement its invasive growth defect. In this
screening, 14 novel genes were isolated. One gene shares highest similarity in amino
acids
(38%) with Srb9 of S. cerevisiae and designated CaSRB9 (Candida albicans SRB9 gene).
The deduced translation production of another gene is belong to a GAL4 fugal
transcription regulatory protein family, which was named CZF2 ( Candida albicans zinc
finger protein). The third gene encoding a cell wall protein was designated CaFLO11.
The CaSRB9 gene has an ORF of 4998 bp, encoding a predicted protein of 1665
amino acids. Ectopic expression of the CaSRB9 gene in diploid S. cerevisiae suppressed
defect in filamentous growth of some mutants in filamentation MAPK pathway (ste7/ste7,
ste12/ste12, and tec1/tec1) and flo8/flo8 mutant under nitrogen starvation conditions. In
haploid S. cerevisiae, ectopic expressed CaSrb9 complemented the invasive growth defect
of flo8 mutant but failed to complement the invasive growth defects of the mutants in
filamentation MAPK pathway.
The CZF2 gene has an ORF of 1875 bp, encoding a deduced protein of 624 amino
acids. Czf2 has a N-terminal conserved Zn2Cys6 zinc cluster motif. The region forms a
binuclear zinc cluster, in which two Zn atoms are bound by six Cys residues . Ectopic
expression of the CZF2 gene in diploid S. cerevisiae partially suppressed defects in
filamentous growth of the mutants in filamentation MAPK pathway and flo8/flo8 mutant
under nitrogen starvation conditions. In haploid S. cerevisiae, ectopic expressed Czf2
complemented the invasive growth defects of the mutants in filamentation MAPK
pathway and flo8 mutant. The deletion of CZF2 gene in C. albicans caused slightly defect
in hyphal formation. czf2/czf2 mutant strain grown in YPD medium formed elongated
cells. These results suggested CZF2 contributed to C. albicans morphogenesis. In a
systemic mouse model, czf2/czf2 mutant strains showed reduced virulence comparing
with wild type strains..
The CaFLO11 gene has an ORF of 1962 bp, encoding a hypothetic protein of 653
amino acids. CaFlo11 is similar in overall structure to the class of yeast serine/threonine
rich GPI-anchored cell wall proteins. An N-terminal domain containing a signal sequence
白色念珠菌在不同的生长条件下能发生显著的形态变化，这种变化由多种调控
因子与信号转导途径所调控。酿酒酵母的G1 期细胞周期蛋白Cln1 和Cln2 参与
了其形态发生，cln1/cln1 cln2/cln2 双缺失株不能形成菌丝。把白色念珠菌基因组
文库导入cln1/cln1 cln2/cln2 缺失株，筛选能校正菌丝形成缺陷的基因，分离得
到白色念珠菌中的CaBEM1 基因。从核苷酸序列推导，CaBEM1 编码一个632
个氨基酸的蛋白，氨基酸序列分析表明在其N 端有两个SH3 结构域，中部有一
个PX结构域，C端有一个PB1结构域；CaBEM1的氨基酸序列与酿酒酵母的Bem1
同源性达38%， 与裂殖酵母的Scd2同源性达32％。 在酿酒酵母的缺失株中异源
表达CaBEM1， 能够部分校正它们在氮源缺乏条件下的菌丝形成缺陷。这种菌
丝形成的校正作用绕过MAPK途径和cAMP/PKA途径，表明CaBem1在菌丝形
成中的作用可能位于这两条信号传导途径的下游。
酿酒酵母Flo8 因子在其形态发生中起重要作用，我们把白色念珠菌基因组
DNA导入酿酒酵母flo8基因缺失株中，筛选能够互补flo8侵入生长缺陷的基因，
分离到了14个新基因，包括CaSRB9， CZF2和CaFLO11等基因。
CaSRB9 基因编码区全长4998 bp， 编码一个1665 个氨基酸的蛋白质。该基
因产物与酿酒酵母SRB9基因编码的产物具有最高的同源性，因此命名为CaSRB9
（C. albicans SRB9）。 在双倍体酿酒酵母中异源表达CaSRB9可以部分校正MAPK
途径基因缺失株以及flo8 缺失株的菌丝生长缺陷；在单倍体酿酒酵母中表达能
够互补flo8 缺失株的侵入生长缺陷，但在MAPK 途径基因缺失株中不能形成侵
入生长。
CZF2 Candida albicans zinc finger protein 基因的编码区为1875bp ，由序列
推断编码一种624个氨基酸的蛋白Czf2， 属于GAL4真菌转录调控蛋白家族。Czf2
的N端有一个保守的Zn2Cys6锌指结构域，这一结构域中有六个半胱氨酸残基，
结合两个锌离子形成结合DNA 的锌簇（zinc cluster）。 在双倍体酿酒酵母中异
源表达CZF2 可以部分校正MAPK 途径基因缺失株以及flo8 缺失株的菌丝生长
缺陷；在单倍体酿酒酵母中异源表达Czf2能够校正MAPK途径基因缺失株以及
flo8缺失株的侵入生长缺陷。用同源重组法敲除了白色念珠菌CZF2基因。czf2/czf2
缺失株在一些固体培养基中有轻微的菌丝形成缺陷。在YPD 中培养时形成伸长
的细胞。表明CZF2 基因的缺失对其形态发生有一定影响。以小鼠系统感染模型
研究发现，czf2/czf2缺失株的毒性比野生型略有下降。
CaFLO11 （C. albicans FLO11） 基因编码区为1962bp， 由序列推断编码一个
653 个氨基酸的蛋白质。从氨基酸序列分析预测CaFlo11 是一个细胞壁蛋白，其
N端有信号肽序列，C末端具有GPI结构域，中部含有多个由丝氨酸和苏氨酸组
成的串联重复序列。在双倍体酿酒酵母中异源表达CaFLO11 可以强烈地激活菌
丝生长，这种激活绕过MAPK 途径以及cAMP/PKA 途径。在单倍体酿酒酵母中
表达能够使MAPK 途径基因缺失株以及flo8 缺失株形成很强的侵入生长。用同
源重组法敲除白色念珠菌CaFLO11 基因，caflo11/caflo11 缺失株没有明显的菌丝
形成缺陷，但在某些液体培养基中形成的菌丝较为粗短。以小鼠系统感染模型
研究发现，CaFLO11的缺失对白色念珠菌的毒性几乎没有影响。
酿酒酵母MAPK 途径成员缺失株biofilm 形成能力降低。外源表达CZF2 和
CaFLO11 能不同程度地校正这些缺失株的biofilm 形成缺陷，但不能校正flo8 缺
失株的biofilm 形成缺陷。CaFLO11 能轻微地校正flo11 缺失株的biofilm 形成缺
陷。
Candida albicans is the most frequently isolated fungal pathogen in humans. The
pathogenic fungus Candida albicans has a dimorphic transition in various environmental
conditions. Many regulatory factors and several transduction pathways have been
identified in controlling filamentous growth. G1 cyclins Cln1 and Cln2 have been reported
as involved in the control of morphogenesis in Saccharomyces cerevisiae. Diploid
cln1/cln1 cln2/cln2 strains completely lost the ability to form pseudohyphae. A C.
albicans genomic DNA library was introduced into cln1/cln1 cln2/cln2 mutant to screen
genes which could complement its filamentous growth defect. In this screening, a BEM1
homolog, CaBEM1, was identified. The CaBEM1 gene has an ORF of 1899 bp, encoding
a putative protein of 632 amino acids. The CaBem1 protein shares highest homology in
amino acids with Bem1(38%) of S. cerevisiae and Scd2(32%) of Schizosaccharomyces
pombe. Sequence analysis showed that the CaBem1 contains two N-terminal SH3
domains, a PX domain and a C-terminal PB1 domain. It is believed these domains are
required for binding to proteins involved in polarized growth in S. cerevisiae and S. pombe.
Ectopic expression of the CaBEM1 gene in diploid S. cerevisiae suppressed defects in
filamentous growth of some mutants under nitrogen starvation conditions. This
suppression bypassed MAPK pathway and cAMP/PKA pathway in filamentous growth.
These results suggest that the CaBem1 protein may be a downstream component of these
two signal transduction pathways for filaments formation.
Flo8 plays an important role in morphogenesis of Saccharomyces cerevisiae. In this
work, a C. albicans genomic DNA library was introduced into an S. cerevisiae flo8/flo8
mutant to screen genes which could complement its invasive growth defect. In this
screening, 14 novel genes were isolated. One gene shares highest similarity in amino
acids
(38%) with Srb9 of S. cerevisiae and designated CaSRB9 (Candida albicans SRB9 gene).
The deduced translation production of another gene is belong to a GAL4 fugal
transcription regulatory protein family, which was named CZF2 ( Candida albicans zinc
finger protein). The third gene encoding a cell wall protein was designated CaFLO11.
The CaSRB9 gene has an ORF of 4998 bp, encoding a predicted protein of 1665
amino acids. Ectopic expression of the CaSRB9 gene in diploid S. cerevisiae suppressed
defect in filamentous growth of some mutants in filamentation MAPK pathway (ste7/ste7,
ste12/ste12, and tec1/tec1) and flo8/flo8 mutant under nitrogen starvation conditions. In
haploid S. cerevisiae, ectopic expressed CaSrb9 complemented the invasive growth defect
of flo8 mutant but failed to complement the invasive growth defects of the mutants in
filamentation MAPK pathway.
The CZF2 gene has an ORF of 1875 bp, encoding a deduced protein of 624 amino
acids. Czf2 has a N-terminal conserved Zn2Cys6 zinc cluster motif. The region forms a
binuclear zinc cluster, in which two Zn atoms are bound by six Cys residues . Ectopic
expression of the CZF2 gene in diploid S. cerevisiae partially suppressed defects in
filamentous growth of the mutants in filamentation MAPK pathway and flo8/flo8 mutant
under nitrogen starvation conditions. In haploid S. cerevisiae, ectopic expressed Czf2
complemented the invasive growth defects of the mutants in filamentation MAPK
pathway and flo8 mutant. The deletion of CZF2 gene in C. albicans caused slightly defect
in hyphal formation. czf2/czf2 mutant strain grown in YPD medium formed elongated
cells. These results suggested CZF2 contributed to C. albicans morphogenesis. In a
systemic mouse model, czf2/czf2 mutant strains showed reduced virulence comparing
with wild type strains..
The CaFLO11 gene has an ORF of 1962 bp, encoding a hypothetic protein of 653
amino acids. CaFlo11 is similar in overall structure to the class of yeast serine/threonine
rich GPI-anchored cell wall proteins. An N-terminal domain containing a signal sequence
引文
[1] Odds FC. Candida and Candidosis. A Review and Bibliography, London: Bailliere Tindal, 1988
[2] Sherer S, Magee P T. Genetics of Candida albicans. Microbiol Rev, 1990, 54:226-241
[3] 吴绍熙. 中国致病真菌流行病学动态研究. In: 廖万清吴绍熙主编. 真菌病研究进展第二军医大学出版社1999, 1–10页
[4] Cutler JE. Putative virulence factors of Candida albicans. Annu Rev Microbiol, 1991, 45:187-218
[5] Kobayashi SC, Cutler JE. Candida albicans hyphal formation and virulence: is there a clearly defined role?. Trends Microbiol. 1998, 6:92-94
[6] Odds FC. Pathogenesis of candida infections. J Am Acad Dermatol, 1994, 31(pt2):s2-5
[7] Odds FC. Morphogenesis in candida albicans, Crit Rev Microbiol., 1985, 12: 45-93
[8] Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR. Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell, 1992, 68:1077–90
[9] Banuett F, Signalling in the yeasts: an informational cascade with links to the filamentous fungi.Microbiol Mol Biol Rev, 1998, 62:249-74
[10] Kohler JR, Fink GR. Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc Natl Acad Sci USA, 1996, 93:13223-28
[11] Leberer E, Harcus D, Broadbent ID, Clark KL, et al. Signal transduction through homologs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida albicans. Proc Natl Acad Sci USA, 1996, 93:13217-22
[12] Whiteway M, Dignard D, Thomas DY. Dominant negative selection of heterologous genes:isolation of Candida albicans genes that interfere with Saccharomyces cerevisiae mating factorinduced cell cycle arrest. Proc Natl Acad Sci USA, 1992, 89:9410-14
[13] Liu H, Kohler J, Fink GR. Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog. Science, 1994, 266:1723-26
[14] Malathi K, Ganesan K, Datta A. Identification of a putative transcription factor in Candida albicans that can complement the mating defect of Saccharomyces cerevisiae ste12 mutants. J Biol Chem, 1994, 269:22945-51
[15] Lorenz MC, Heitman J. Yeast pseudohyphal growth is regulated by GPA2, a G protein a homolog.EMBO J 1997, 16:7008-7018
[16] Kübler E, M?sch HU, Rupp S, Lisanti MP. Gpa2p, a G-protein alpha-subunit, regulates growth and pseudohyphal development in Saccharomyces cerevisiae via a cAMP-dependent mechanism.J Biol Chem 1997, 272:20321-20323
[17] Lorenz MC, Pan X, Harashima T, Cardenas ME, Xue Y, Hirsch JP, Heitman J. The G proteincoupled receptor GPR1 is a nutrient sensor that regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Genetics 2000, 154:609-622
[18] Pan X, Heitman J. Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol Cell Biol 1999, 19:4874-4887
[19] Rupp S, Summers E, Lo H, Madhani H, Fink G. MAP kinase and cAMP filamentation signaling pathways converge on the unusually large promoter of the yeast FLO11 gene. EMBO J 1999, 18:1257-1269
[20] Robertson LS, Fink GR. The three yeast A kinases have specific signaling functions in pseudohyphal growth. Proc Natl Acad Sci USA 1998, 95:13783-13787
[21] Song W, Carlson M. Srb/mediator proteins interact functionally and physically with transcriptional repressor Sfl1. EMBO J. 1998, 1;17(19):5757-65
[22] Pan X, Heitman J. Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Mol Cell Biol, 2002, 22(12):3981-93
[23] Liu H. Transcriptional control of dimorphism in Candida albicans. Curr Opin Microbiol. 2001, 4(6):728-35
[24] Bahn YS, Sundstrom P. CAP1, an adenylate cyclase-associated protein gene, regulates bud-hypha transitions, filamentous growth, and cyclic AMP levels and is required for virulence of Candida albicans.J Bacteriol. 2001,183(10):3211-23
[25] Feng Q, Summers E, Guo B, Fink G. Ras signaling is required for serum-induced hyphal differentiation in Candida albicans.J Bacteriol. 1999,181(20):6339-46
[26] Sonneborn A, Bockmuhl DP, Gerads M, Kurpanek K, Sanglard D, Ernst JF. Protein kinase A encoded by TPK2 regulates dimorphism of Candida albicans. Mol Microbiol. 2000, 35(2):386-96
[27] Lo HJ, Kohler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR: Nonfilamentous C. albicans mutants are avirulent. Cell 1997, 90:939-949
[28] Stoldt VR, Sonneborn A, Leuker CE, Ernst JF: Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J 1997, 16:1982-1991
[29] Pan X, Heitman J: Sok2 regulates yeast pseudohyphal differentiation via a transcription factor cascade that regulates cell–cell adhesion. Mol Cell Biol 2000, 20:8364-8372.
[30] Shenhar G, Kassir Y: A positive regulator of mitosis, Sok2, functions as a negative regulator of meiosis in Saccharomyces cerevisiae. Mol Cell Biol 2001, 21:1603-1612.
[31] Bockmuhl DP, Ernst JF: A potential phosphorylation site for an A type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans. Genetics 2001, 157:1523-1530
[32] Leng P, Lee PR, Wu H, Brown AJ: Efg1, a morphogenetic regulator in Candida albicans, is a sequence-specific DNA binding protein. J Bacteriol 2001, 183:4090-4093.
[33] Chen J, Zhou S, Wang Q, Chen X, Pan T, Liu H: Crk1, a novel Cdc2 related protein kinase, is required for hyphal development and virulence in Candida albicans. Mol Cell Biol 2000, 20:8696-8708
[34] Gorner W, Durchschlag E, Martinez-Pastor MT, Estruch F, Ammerer G, Hamilton B, Ruis H, Schuller C: Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev 1998, 12:586-597.
[35] Conlan RS, Tzamarias D: Sfl1 functions via the co-repressor Ssn6-Tup1 and the cAMP-dependent protein kinase Tpk2. J Mol Biol 2001, 309:1007-1015.
[36] Schweizer A, Rupp S, Taylor BN, Rollinghoff M, Schroppel K: The TEA/ATTS transcription factor CaTec1p regulates hyphal development and virulence in Candida albicans. Mol Microbiol 2000, 38:435-445
[37] Lane S, Zhou S, Pan T, Dai Q, Liu H: The basic helix-loop-helix transcription factor cph2 regulates hyphal development in Candida albicans partly via Tec1. Mol Cell Biol 2001, 21:6418- 428
[38] Braun BR, Johnson AD: TUP1, CPH1 and EFG1 make independent contributions to filamentation in Candida albicans. Genetics 2000, 155:57-67.
[39] Kadosh D, Johnson AD: Rfg1, a protein related to the Saccharomyces cerevisiae hypoxic regulator Rox1, controls filamentous growth and virulence in Candida albicans. Mol Cell Biol 2001, 21:2496-2505
[40] Khalaf RA, Zitomer RS: The DNA binding protein Rfg1 is a repressor of filamentation in Candida albicans. Genetics 2001, 157:1503-1512
[41] Murad AM, Leng P, Straffon M, Wishart J, Macaskill S, MacCallum D, Schnell N, Talibi D,Marechal D, Tekaia F et al.: NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans. EMBO J 2001, 20:4742-4752
[42] Braun BR, Kadosh D, Johnson AD: NRG1, a repressor of filamentous growth in C. albicans, is down-regulated during filament induction. EMBO J 2001, 20:4753-4761
[43] Porta A, Ramon AM, Fonzi WA: PRR1, a homolog of Aspergillus nidulans palF, controls pHdependent gene expression and filamentation in Candida albicans. J Bacteriol 1999, 181:7516-7523.
[44] Ramon A, Porta A, Fonzi WA: Effects of environmental pH on morphological development of Candida albicans is mediated via the PacC-related transcription factor encoded by PRR2. J Bacteriol 1999, 181:7524-7530.
[45] Davis D, Wilson RB, Mitchell AP: RIM101-dependent and -independent pathways govern pH responses in Candida albicans. Mol Cell Biol 2000, 20:971-978.
[46] El Barkani A, Kurzai O, Fonzi WA, Ramon A, Porta A, Frosch M, Muhlschlegel FA: Dominant active alleles of RIM101 (PRR2) bypass the pH restriction on filamentation of Candida albicans. Mol Cell Biol 2000, 20:4635-4647.
[47] Sharkey LL, McNemar MD, Saporito-Irwin SM, Sypherd PS, Fonzi WA: HWP1 functions in the morphological development of Candida albicans downstream of EFG1, TUP1, and RBF1. J Bacteriol 1999, 181:5273-5279.
[48] Schroppel K, Sprosser K, Whiteway M, Thomas DY, Rollinghoff M, Csank C: Repression of hyphal proteinase expression by the mitogen-activated protein (MAP) kinase phosphatase Cpp1p of Candida albicans is independent of the MAP kinase Cek1p. Infect Immun 2000, 68:7159-7161.
[49] Anderson JM, Soll DR: Differences in actin localization during bud and hypha formation in the yeast Candida albicans. J Gen Microbiol 1986, 132:2035-2047.
[50] Wendland J, Philippsen P: Cell polarity and hyphal morphogenesis are controlled by multiple rhoprotein modules in the filamentous ascomycete Ashbya gossypii. Genetics 2001, 157:601-610.
[51] 46. Leberer E, Ziegelbauer K, Schmidt A, Harcus D, Dignard D, Ash J, Johnson L, Thomas DY: Virulence and hyphal formation of Candida albicans require the Ste20p-like protein kinase CaCla4p. Curr Biol 1997, 7:539-546.
[52] Brown DH Jr, Giusani AD, Chen X, Kumamoto CA: Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol Microbiol 1999, 34:651-662
[53] Ishii N, Yamamoto M, Yoshihara F, Arisawa M, Aoki Y. Biochemical and genetic characterization of Rbf1p, a putative transcription factor of Candida albicans. Microbiology, 1997, 143:429–35
[54] Staab JF, Bradway SD, Fidel PL, Sundstrom P: Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 1999, 283:1535-1538.
[55] Birse CE, Irwin MY, Fonzi, W A, Sypherd P S. Cloning and characterization of ECE1, a gene expressed in association with cell elongation of the dimorphic pathogen Candida albicans . Infect Immun, 1993, 61: 3648-3655
[56] Bailey DA, Feldmann PJ, Bovey M, Gow NA, et al. The Candida albicans HYR1 gene, whick is activated in response to hyphal development, belongs to a gene family encoding yeast cell wall protiens. J Bacteriol, 1996, 178(18):5353-60
[57] Staab JF, Bradway SD, Fidel PL, Sundstrom P: Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 1999, 283:1535-1538
[58] Ayad-Durieux Y, Knechtle P, Goff S, Dietrich F, Philippsen P: A PAKlike protein kinase is required for maturation of young hyphae and septation in the filamentous ascomycete Ashbya gossypii. J Cell Sci 2000, 113:4563-4575
[59] Csank C, Makris C, Meloche S, Schrouml K, et al. Derepressed Hyphal Growth and Reduced Virulence in a VH1 Family-related Protein Phosphatase Mutant of the Human Pathogen Candida albicans. Mol. Biol Cell, 1997, 8:2539-51
[60] Baillie GS, Douglas LJ. 1999. Role of dimorphism in the development of Candida albicans biofilms. J. Med. Microbiol. 48:671–79
[61] Jarvis WR, Martone WJ. Predominant pathogens in hospital infections. J Antimicrob Chemother,1992, 29:19–24
[62] 吴绍熙. 抗真菌药的研究进展. In: 廖万清吴绍熙主编. 真菌病研究进展第二军医大学出版社1999, 15–19页
[63] 陈江汉. 念珠菌病. In: 廖万清吴绍熙主编. 真菌病研究进展第二军医大学出版社1999,80–94页
[64] Madden K, Snyder M. Cell polarity and morphogenesis in budding yeast. Annu Rev Microbiol ,1998, 52:687-744
[65] Chant J. Cell polarity in yeast. Annu Rev Cell Dev Biol, 1999, 15:365-391
[66] Nern A, Arkowitz RA. A GTP-exchange factor required for cell orientation. Nature, 1998, 391(6663):195-198
[67] Park HO, Bi E, Pringle JR, Herskowitz I. Two active states of the Ras-related Bud1/Rsr1 protein bind to different effectors to determine yeast cell polarity. Proc Natl Acad Sci USA, 1997, 94(9):4463-4468
[68] Leberer E, Chenevert J, Leeuw T, Harcus D, Herskowitz I, Thomas DY. Genetic interactions indicate a role for Mdg1p and the SH3 domain protein Bem1p in linking the G-protein mediated yeast pheromone signalling pathway to regulators of cell polarity. Mol Gen Genet, 1996, 252(5):608-621
[69] Butty AC, Pryciak PM, Huang LS, Herskowitz I, Peter M. The role of Far1p in linking the heterotrimeric G protein to polarity establishment proteins during yeast mating. Science, 1998, 282(5393):1511-1516
[70] Loeb JD, Kerentseva TA, Pan T, Sepulveda-Becerra M, Liu H. Saccharomyces cerevisiae G1 cyclins are differentially involved in invasive and pseudohyphal growth independent of the filamentation mitogen-activated protein kinase pathway. Genetics, 1999, 153(4):1535-1546
[71] Liu H, Styles CA, Fink GR. Elements of the yeast pheromone response pathway required for filamentous growth of diploids. Science, 1993, 262:1741-1744
[72] Liu H, Styles CA, Fink GR. Saccharomyces cerevisiae S288C has a mutation in FLO8, a gene required for filamentous growth. Genetics, 1996, 144:967-978
[73] Lane S, Birse C, Zhou S, Matson R, Liu H. DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans. J Biol Chem. 2001,276(52):48988-96
[74] Vernet T, Dignard D, Thomas DY. A family of yeast expression vectors containing the phage f1 intergenic region. Gene, 1987, 52:225-233
[75] Lee K L, Buckley H R, Campbell C C. An amino acid liquid synthetic medium for the development of mycelial and yeast forms of Candida albicans. Sabouraudia, 1975, 12:148-153
[76] http://alces.med.umn.edu/candida/methods.htm
[77] Wang Q, Zhou S, Chen J Y. Functions of CRK1 gene of Candida albicans as studied by gene knock-out, Acta Biochim Biophys Sin,, 1999, 31(5): 545-552
[78] Zhou S, Wang Q, Chen J, Chen J Y. Molecular cloning of MAPK gene family using synthetic oligonucleotide probe, Acta Biochim Biophys Sin, 1999, 31(5): 537-544
[79] Ausubel F M, Short protocols in molecular biology. New York: John Wiley & Sons, 1994
[80] Chen J, Ni J, Chen JY. Molecular cloning of MAPK gene family using degenerate PCR. Acta Biochem Biophys Sin, 2000, 32(3):305-311
[81] Bernardis F, Muhlschlegel FA, Cassone A, Fonzi WA. The pH of the host niche controls gene expression in and virulence of Candida albicans. Infec Immun, 1998, 66(7):3317-3325
[82] Reynolds TB, Fink GR.Bakers' yeast, a model for fungal biofilm formation. Science. 2001, 291(5505):878-81
[83] Musacchio A, Gibson T, Lehto VP, Saraste M. SH3--an abundant protein domain in search of a function. FEBS Lett, 1992, 307(1):55-61
[84] Lock P, Abram CL, Gibson T, Courtneidge SA. A new method for isolating tyrosine kinase substrates used to identify fish, an SH3 and PX domain-containing protein, and Src substrate. EMBO J, 1998, 17(15):4346-4357
[85] Ponting CP. Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: Binding partners of SH3 domains? Protein Sci, 1996, 5(11):2353-2357
[86] Ago T, Takeya R, Hiroaki H, Kuribayashi F, Ito T, Kohda D, Sumimoto H. The PX domain as a novel phosphoinositide-binding module. Biochem Biophys Res Commun, 2001, 287(3):733-738
[87] Ito T, Matsui Y, Ago T, Ota K, Sumimoto H. Novel modular domain PB1 recognizes PC motif to mediate functional protein-protein interactions. EMBO J, 2001, 20(15):3938-3946
[88] Terasawa H, Noda Y, Ito T, Hatanaka H, Ichikawa S, Ogura K, Sumimoto H et al. Structure and ligand recognition of the PB1 domain: A novel protein module binding to the PC motif. EMBO J, 2001, 20(15):3947-3956
[89] Elion EA. Pheromone response, mating and cell biology. Curr Opin Microbiol, 2000, 3(6):573-581
[90] Chang E, Bartholomeusz G, Pimental R, Chen J, Lai H, Wang L, Yang P, Marcus S. Direct binding and in vivo regulation of the fission yeast p21-activated kinase shk1 by the SH3 domain proteinscd2. Mol Cell Biol, 1999, 19(12):8066-8074
[91] Mirbod F, Nakashima S, Kitajima Y, Cannon RD, Nozawa Y. Molecular cloning of a Rho family,CDC42Ca gene from Candida albicans and its mRNA expression changes during morphogenesis. J Med Vet Mycol, 1997, 35(3):173-179
[92] Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR. Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: Regulation by starvation and RAS. Cell, 1992, 68(6):1077-1090
[93] Madhani HD, Fink GR.The control of filamentous differentiation and virulence in fungi. Trends Cell Biol, 1998, 8(9):348-53
[94] Cullen PJ, Sprague GF Jr. Glucose depletion causes haploid invasive growth in yeast. Proc Natl Acad Sci USA. 2000, 97(25):13619-13624
[95] Song W, Treich I, Qian N, Kuchin S, Carlson M. SSN genes that affect transcriptional repression in Saccharomyces cerevisiae encode SIN4, ROX3, and SRB proteins associated with RNA polymerase II. Mol Cell Biol, 1996, 16:115-120
[96] Carlson M. Genetics of transcriptional regulation in yeast: Connections to the RNA polymerase II CTD. Annu Rev Cell Dev Biol, 1997, 13:1-23
[97] Tabtiang RK, Herskowitz I. Nuclear proteins Nut1p and Nut2p cooperate to negatively regulate a Swi4p-dependent lacZ reporter gene in Saccharomyces cerevisiae. Mol Cell Biol, 1998, 18: 4707- 4718
[98] Strich R, Slater MR, Esposito RE. Identification of negative regulatory genes that govern the expression of early meiotic genes in yeast. Proc Natl Acad Sci USA, 1989, 86:10018-10022
[99] Chang YW, Howard SC, Budovskaya YV, Rine J, Herman PK. The rye mutants identify a role for Ssn/Srb proteins of the RNA polymerase II holoenzyme during stationary phase entry in Saccharomyces cerevisiae. Genetics, 2001, 157:17-26
[100] Pan,T., Coleman,J.E., GAL4 transcription factor is not a 'zinc finger' but forms a Zn(II)2Cys6 binuclear cluster. (1990) Proc. Natl. Acad. Sci. U.S.A. 87: 2077-2081
[101] Harrison,S.C., Marmorstein,R., Carey,M., Ptashne,M., DNA recognition by GAL4: structure of a protein-DNA complex. (1992) Nature 356: 408-414
[102] Schjerling P, Holmberg S.Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators.Nucleic Acids Res. 1996, 24(23): 4599-607
[103] Watari J, Takata Y, Ogawa M, Sahara H, Koshino S, Onnela ML, Airaksinen U, Jaatinen R, Penttila M, Keranen S. Molecular cloning and analysis of the yeast flocculation gene FLO1. Yeast. 1994, 10(2): 211-25
[104] Hauser K, Tanner W. Purification of the inducible α-agglutinin of S. cerevisiae and molecular cloning of the gene. FEBS Lett. 1989, 255(2): 290-4
[105] Lipke PN, Chen MH, de Nobel H, Kurjan J, Kahn PC. Homology modeling of an immunoglobulin-like domain in the Saccharomyces cerevisiae adhesion protein α- agglutinin.Protein Sci. 1995, 4(10): 2168-78
[106] Nuoffer C, Jeno P, Conzelmann A, Riezman H. Determinants for glycophospholipid anchoring of the Saccharomyces cerevisiae GAS1 protein to the plasma membrane. Mol Cell Biol. 1991, 11(1): 27-37
[107] Vai M, Gatti E, Lacana E, Popolo L, Alberghina L. Isolation and deduced amino acid sequence of the gene encoding gp115, a yeast glycophospholipid-anchored protein containing a serine-rich region. J Biol Chem. 1991, 266(19): 12242-8
[108] Wilson RB, Davis D, Mitchell AP. Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions.J Bacteriol. 1999, 181(6):1868-74
[109] Loeb JD, Sepulveda-Becerra M, Hazan I, Liu H. A G1 cyclin is necessary for maintenance of filamentous growth in Candida albicans. Mol Cell Biol 1999, 19(6):4019-27
[110] O'Toole G, Kaplan HB, Kolter R. Biofilm formation as microbial development. Annu Rev Microbiol. 2000;54:49-79. Review.
[2] Sherer S, Magee P T. Genetics of Candida albicans. Microbiol Rev, 1990, 54:226-241
[3] 吴绍熙. 中国致病真菌流行病学动态研究. In: 廖万清吴绍熙主编. 真菌病研究进展第二军医大学出版社1999, 1–10页
[4] Cutler JE. Putative virulence factors of Candida albicans. Annu Rev Microbiol, 1991, 45:187-218
[5] Kobayashi SC, Cutler JE. Candida albicans hyphal formation and virulence: is there a clearly defined role?. Trends Microbiol. 1998, 6:92-94
[6] Odds FC. Pathogenesis of candida infections. J Am Acad Dermatol, 1994, 31(pt2):s2-5
[7] Odds FC. Morphogenesis in candida albicans, Crit Rev Microbiol., 1985, 12: 45-93
[8] Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR. Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell, 1992, 68:1077–90
[9] Banuett F, Signalling in the yeasts: an informational cascade with links to the filamentous fungi.Microbiol Mol Biol Rev, 1998, 62:249-74
[10] Kohler JR, Fink GR. Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc Natl Acad Sci USA, 1996, 93:13223-28
[11] Leberer E, Harcus D, Broadbent ID, Clark KL, et al. Signal transduction through homologs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida albicans. Proc Natl Acad Sci USA, 1996, 93:13217-22
[12] Whiteway M, Dignard D, Thomas DY. Dominant negative selection of heterologous genes:isolation of Candida albicans genes that interfere with Saccharomyces cerevisiae mating factorinduced cell cycle arrest. Proc Natl Acad Sci USA, 1992, 89:9410-14
[13] Liu H, Kohler J, Fink GR. Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog. Science, 1994, 266:1723-26
[14] Malathi K, Ganesan K, Datta A. Identification of a putative transcription factor in Candida albicans that can complement the mating defect of Saccharomyces cerevisiae ste12 mutants. J Biol Chem, 1994, 269:22945-51
[15] Lorenz MC, Heitman J. Yeast pseudohyphal growth is regulated by GPA2, a G protein a homolog.EMBO J 1997, 16:7008-7018
[16] Kübler E, M?sch HU, Rupp S, Lisanti MP. Gpa2p, a G-protein alpha-subunit, regulates growth and pseudohyphal development in Saccharomyces cerevisiae via a cAMP-dependent mechanism.J Biol Chem 1997, 272:20321-20323
[17] Lorenz MC, Pan X, Harashima T, Cardenas ME, Xue Y, Hirsch JP, Heitman J. The G proteincoupled receptor GPR1 is a nutrient sensor that regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Genetics 2000, 154:609-622
[18] Pan X, Heitman J. Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol Cell Biol 1999, 19:4874-4887
[19] Rupp S, Summers E, Lo H, Madhani H, Fink G. MAP kinase and cAMP filamentation signaling pathways converge on the unusually large promoter of the yeast FLO11 gene. EMBO J 1999, 18:1257-1269
[20] Robertson LS, Fink GR. The three yeast A kinases have specific signaling functions in pseudohyphal growth. Proc Natl Acad Sci USA 1998, 95:13783-13787
[21] Song W, Carlson M. Srb/mediator proteins interact functionally and physically with transcriptional repressor Sfl1. EMBO J. 1998, 1;17(19):5757-65
[22] Pan X, Heitman J. Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Mol Cell Biol, 2002, 22(12):3981-93
[23] Liu H. Transcriptional control of dimorphism in Candida albicans. Curr Opin Microbiol. 2001, 4(6):728-35
[24] Bahn YS, Sundstrom P. CAP1, an adenylate cyclase-associated protein gene, regulates bud-hypha transitions, filamentous growth, and cyclic AMP levels and is required for virulence of Candida albicans.J Bacteriol. 2001,183(10):3211-23
[25] Feng Q, Summers E, Guo B, Fink G. Ras signaling is required for serum-induced hyphal differentiation in Candida albicans.J Bacteriol. 1999,181(20):6339-46
[26] Sonneborn A, Bockmuhl DP, Gerads M, Kurpanek K, Sanglard D, Ernst JF. Protein kinase A encoded by TPK2 regulates dimorphism of Candida albicans. Mol Microbiol. 2000, 35(2):386-96
[27] Lo HJ, Kohler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR: Nonfilamentous C. albicans mutants are avirulent. Cell 1997, 90:939-949
[28] Stoldt VR, Sonneborn A, Leuker CE, Ernst JF: Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J 1997, 16:1982-1991
[29] Pan X, Heitman J: Sok2 regulates yeast pseudohyphal differentiation via a transcription factor cascade that regulates cell–cell adhesion. Mol Cell Biol 2000, 20:8364-8372.
[30] Shenhar G, Kassir Y: A positive regulator of mitosis, Sok2, functions as a negative regulator of meiosis in Saccharomyces cerevisiae. Mol Cell Biol 2001, 21:1603-1612.
[31] Bockmuhl DP, Ernst JF: A potential phosphorylation site for an A type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans. Genetics 2001, 157:1523-1530
[32] Leng P, Lee PR, Wu H, Brown AJ: Efg1, a morphogenetic regulator in Candida albicans, is a sequence-specific DNA binding protein. J Bacteriol 2001, 183:4090-4093.
[33] Chen J, Zhou S, Wang Q, Chen X, Pan T, Liu H: Crk1, a novel Cdc2 related protein kinase, is required for hyphal development and virulence in Candida albicans. Mol Cell Biol 2000, 20:8696-8708
[34] Gorner W, Durchschlag E, Martinez-Pastor MT, Estruch F, Ammerer G, Hamilton B, Ruis H, Schuller C: Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev 1998, 12:586-597.
[35] Conlan RS, Tzamarias D: Sfl1 functions via the co-repressor Ssn6-Tup1 and the cAMP-dependent protein kinase Tpk2. J Mol Biol 2001, 309:1007-1015.
[36] Schweizer A, Rupp S, Taylor BN, Rollinghoff M, Schroppel K: The TEA/ATTS transcription factor CaTec1p regulates hyphal development and virulence in Candida albicans. Mol Microbiol 2000, 38:435-445
[37] Lane S, Zhou S, Pan T, Dai Q, Liu H: The basic helix-loop-helix transcription factor cph2 regulates hyphal development in Candida albicans partly via Tec1. Mol Cell Biol 2001, 21:6418- 428
[38] Braun BR, Johnson AD: TUP1, CPH1 and EFG1 make independent contributions to filamentation in Candida albicans. Genetics 2000, 155:57-67.
[39] Kadosh D, Johnson AD: Rfg1, a protein related to the Saccharomyces cerevisiae hypoxic regulator Rox1, controls filamentous growth and virulence in Candida albicans. Mol Cell Biol 2001, 21:2496-2505
[40] Khalaf RA, Zitomer RS: The DNA binding protein Rfg1 is a repressor of filamentation in Candida albicans. Genetics 2001, 157:1503-1512
[41] Murad AM, Leng P, Straffon M, Wishart J, Macaskill S, MacCallum D, Schnell N, Talibi D,Marechal D, Tekaia F et al.: NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans. EMBO J 2001, 20:4742-4752
[42] Braun BR, Kadosh D, Johnson AD: NRG1, a repressor of filamentous growth in C. albicans, is down-regulated during filament induction. EMBO J 2001, 20:4753-4761
[43] Porta A, Ramon AM, Fonzi WA: PRR1, a homolog of Aspergillus nidulans palF, controls pHdependent gene expression and filamentation in Candida albicans. J Bacteriol 1999, 181:7516-7523.
[44] Ramon A, Porta A, Fonzi WA: Effects of environmental pH on morphological development of Candida albicans is mediated via the PacC-related transcription factor encoded by PRR2. J Bacteriol 1999, 181:7524-7530.
[45] Davis D, Wilson RB, Mitchell AP: RIM101-dependent and -independent pathways govern pH responses in Candida albicans. Mol Cell Biol 2000, 20:971-978.
[46] El Barkani A, Kurzai O, Fonzi WA, Ramon A, Porta A, Frosch M, Muhlschlegel FA: Dominant active alleles of RIM101 (PRR2) bypass the pH restriction on filamentation of Candida albicans. Mol Cell Biol 2000, 20:4635-4647.
[47] Sharkey LL, McNemar MD, Saporito-Irwin SM, Sypherd PS, Fonzi WA: HWP1 functions in the morphological development of Candida albicans downstream of EFG1, TUP1, and RBF1. J Bacteriol 1999, 181:5273-5279.
[48] Schroppel K, Sprosser K, Whiteway M, Thomas DY, Rollinghoff M, Csank C: Repression of hyphal proteinase expression by the mitogen-activated protein (MAP) kinase phosphatase Cpp1p of Candida albicans is independent of the MAP kinase Cek1p. Infect Immun 2000, 68:7159-7161.
[49] Anderson JM, Soll DR: Differences in actin localization during bud and hypha formation in the yeast Candida albicans. J Gen Microbiol 1986, 132:2035-2047.
[50] Wendland J, Philippsen P: Cell polarity and hyphal morphogenesis are controlled by multiple rhoprotein modules in the filamentous ascomycete Ashbya gossypii. Genetics 2001, 157:601-610.
[51] 46. Leberer E, Ziegelbauer K, Schmidt A, Harcus D, Dignard D, Ash J, Johnson L, Thomas DY: Virulence and hyphal formation of Candida albicans require the Ste20p-like protein kinase CaCla4p. Curr Biol 1997, 7:539-546.
[52] Brown DH Jr, Giusani AD, Chen X, Kumamoto CA: Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol Microbiol 1999, 34:651-662
[53] Ishii N, Yamamoto M, Yoshihara F, Arisawa M, Aoki Y. Biochemical and genetic characterization of Rbf1p, a putative transcription factor of Candida albicans. Microbiology, 1997, 143:429–35
[54] Staab JF, Bradway SD, Fidel PL, Sundstrom P: Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 1999, 283:1535-1538.
[55] Birse CE, Irwin MY, Fonzi, W A, Sypherd P S. Cloning and characterization of ECE1, a gene expressed in association with cell elongation of the dimorphic pathogen Candida albicans . Infect Immun, 1993, 61: 3648-3655
[56] Bailey DA, Feldmann PJ, Bovey M, Gow NA, et al. The Candida albicans HYR1 gene, whick is activated in response to hyphal development, belongs to a gene family encoding yeast cell wall protiens. J Bacteriol, 1996, 178(18):5353-60
[57] Staab JF, Bradway SD, Fidel PL, Sundstrom P: Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 1999, 283:1535-1538
[58] Ayad-Durieux Y, Knechtle P, Goff S, Dietrich F, Philippsen P: A PAKlike protein kinase is required for maturation of young hyphae and septation in the filamentous ascomycete Ashbya gossypii. J Cell Sci 2000, 113:4563-4575
[59] Csank C, Makris C, Meloche S, Schrouml K, et al. Derepressed Hyphal Growth and Reduced Virulence in a VH1 Family-related Protein Phosphatase Mutant of the Human Pathogen Candida albicans. Mol. Biol Cell, 1997, 8:2539-51
[60] Baillie GS, Douglas LJ. 1999. Role of dimorphism in the development of Candida albicans biofilms. J. Med. Microbiol. 48:671–79
[61] Jarvis WR, Martone WJ. Predominant pathogens in hospital infections. J Antimicrob Chemother,1992, 29:19–24
[62] 吴绍熙. 抗真菌药的研究进展. In: 廖万清吴绍熙主编. 真菌病研究进展第二军医大学出版社1999, 15–19页
[63] 陈江汉. 念珠菌病. In: 廖万清吴绍熙主编. 真菌病研究进展第二军医大学出版社1999,80–94页
[64] Madden K, Snyder M. Cell polarity and morphogenesis in budding yeast. Annu Rev Microbiol ,1998, 52:687-744
[65] Chant J. Cell polarity in yeast. Annu Rev Cell Dev Biol, 1999, 15:365-391
[66] Nern A, Arkowitz RA. A GTP-exchange factor required for cell orientation. Nature, 1998, 391(6663):195-198
[67] Park HO, Bi E, Pringle JR, Herskowitz I. Two active states of the Ras-related Bud1/Rsr1 protein bind to different effectors to determine yeast cell polarity. Proc Natl Acad Sci USA, 1997, 94(9):4463-4468
[68] Leberer E, Chenevert J, Leeuw T, Harcus D, Herskowitz I, Thomas DY. Genetic interactions indicate a role for Mdg1p and the SH3 domain protein Bem1p in linking the G-protein mediated yeast pheromone signalling pathway to regulators of cell polarity. Mol Gen Genet, 1996, 252(5):608-621
[69] Butty AC, Pryciak PM, Huang LS, Herskowitz I, Peter M. The role of Far1p in linking the heterotrimeric G protein to polarity establishment proteins during yeast mating. Science, 1998, 282(5393):1511-1516
[70] Loeb JD, Kerentseva TA, Pan T, Sepulveda-Becerra M, Liu H. Saccharomyces cerevisiae G1 cyclins are differentially involved in invasive and pseudohyphal growth independent of the filamentation mitogen-activated protein kinase pathway. Genetics, 1999, 153(4):1535-1546
[71] Liu H, Styles CA, Fink GR. Elements of the yeast pheromone response pathway required for filamentous growth of diploids. Science, 1993, 262:1741-1744
[72] Liu H, Styles CA, Fink GR. Saccharomyces cerevisiae S288C has a mutation in FLO8, a gene required for filamentous growth. Genetics, 1996, 144:967-978
[73] Lane S, Birse C, Zhou S, Matson R, Liu H. DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans. J Biol Chem. 2001,276(52):48988-96
[74] Vernet T, Dignard D, Thomas DY. A family of yeast expression vectors containing the phage f1 intergenic region. Gene, 1987, 52:225-233
[75] Lee K L, Buckley H R, Campbell C C. An amino acid liquid synthetic medium for the development of mycelial and yeast forms of Candida albicans. Sabouraudia, 1975, 12:148-153
[76] http://alces.med.umn.edu/candida/methods.htm
[77] Wang Q, Zhou S, Chen J Y. Functions of CRK1 gene of Candida albicans as studied by gene knock-out, Acta Biochim Biophys Sin,, 1999, 31(5): 545-552
[78] Zhou S, Wang Q, Chen J, Chen J Y. Molecular cloning of MAPK gene family using synthetic oligonucleotide probe, Acta Biochim Biophys Sin, 1999, 31(5): 537-544
[79] Ausubel F M, Short protocols in molecular biology. New York: John Wiley & Sons, 1994
[80] Chen J, Ni J, Chen JY. Molecular cloning of MAPK gene family using degenerate PCR. Acta Biochem Biophys Sin, 2000, 32(3):305-311
[81] Bernardis F, Muhlschlegel FA, Cassone A, Fonzi WA. The pH of the host niche controls gene expression in and virulence of Candida albicans. Infec Immun, 1998, 66(7):3317-3325
[82] Reynolds TB, Fink GR.Bakers' yeast, a model for fungal biofilm formation. Science. 2001, 291(5505):878-81
[83] Musacchio A, Gibson T, Lehto VP, Saraste M. SH3--an abundant protein domain in search of a function. FEBS Lett, 1992, 307(1):55-61
[84] Lock P, Abram CL, Gibson T, Courtneidge SA. A new method for isolating tyrosine kinase substrates used to identify fish, an SH3 and PX domain-containing protein, and Src substrate. EMBO J, 1998, 17(15):4346-4357
[85] Ponting CP. Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: Binding partners of SH3 domains? Protein Sci, 1996, 5(11):2353-2357
[86] Ago T, Takeya R, Hiroaki H, Kuribayashi F, Ito T, Kohda D, Sumimoto H. The PX domain as a novel phosphoinositide-binding module. Biochem Biophys Res Commun, 2001, 287(3):733-738
[87] Ito T, Matsui Y, Ago T, Ota K, Sumimoto H. Novel modular domain PB1 recognizes PC motif to mediate functional protein-protein interactions. EMBO J, 2001, 20(15):3938-3946
[88] Terasawa H, Noda Y, Ito T, Hatanaka H, Ichikawa S, Ogura K, Sumimoto H et al. Structure and ligand recognition of the PB1 domain: A novel protein module binding to the PC motif. EMBO J, 2001, 20(15):3947-3956
[89] Elion EA. Pheromone response, mating and cell biology. Curr Opin Microbiol, 2000, 3(6):573-581
[90] Chang E, Bartholomeusz G, Pimental R, Chen J, Lai H, Wang L, Yang P, Marcus S. Direct binding and in vivo regulation of the fission yeast p21-activated kinase shk1 by the SH3 domain proteinscd2. Mol Cell Biol, 1999, 19(12):8066-8074
[91] Mirbod F, Nakashima S, Kitajima Y, Cannon RD, Nozawa Y. Molecular cloning of a Rho family,CDC42Ca gene from Candida albicans and its mRNA expression changes during morphogenesis. J Med Vet Mycol, 1997, 35(3):173-179
[92] Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR. Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: Regulation by starvation and RAS. Cell, 1992, 68(6):1077-1090
[93] Madhani HD, Fink GR.The control of filamentous differentiation and virulence in fungi. Trends Cell Biol, 1998, 8(9):348-53
[94] Cullen PJ, Sprague GF Jr. Glucose depletion causes haploid invasive growth in yeast. Proc Natl Acad Sci USA. 2000, 97(25):13619-13624
[95] Song W, Treich I, Qian N, Kuchin S, Carlson M. SSN genes that affect transcriptional repression in Saccharomyces cerevisiae encode SIN4, ROX3, and SRB proteins associated with RNA polymerase II. Mol Cell Biol, 1996, 16:115-120
[96] Carlson M. Genetics of transcriptional regulation in yeast: Connections to the RNA polymerase II CTD. Annu Rev Cell Dev Biol, 1997, 13:1-23
[97] Tabtiang RK, Herskowitz I. Nuclear proteins Nut1p and Nut2p cooperate to negatively regulate a Swi4p-dependent lacZ reporter gene in Saccharomyces cerevisiae. Mol Cell Biol, 1998, 18: 4707- 4718
[98] Strich R, Slater MR, Esposito RE. Identification of negative regulatory genes that govern the expression of early meiotic genes in yeast. Proc Natl Acad Sci USA, 1989, 86:10018-10022
[99] Chang YW, Howard SC, Budovskaya YV, Rine J, Herman PK. The rye mutants identify a role for Ssn/Srb proteins of the RNA polymerase II holoenzyme during stationary phase entry in Saccharomyces cerevisiae. Genetics, 2001, 157:17-26
[100] Pan,T., Coleman,J.E., GAL4 transcription factor is not a 'zinc finger' but forms a Zn(II)2Cys6 binuclear cluster. (1990) Proc. Natl. Acad. Sci. U.S.A. 87: 2077-2081
[101] Harrison,S.C., Marmorstein,R., Carey,M., Ptashne,M., DNA recognition by GAL4: structure of a protein-DNA complex. (1992) Nature 356: 408-414
[102] Schjerling P, Holmberg S.Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators.Nucleic Acids Res. 1996, 24(23): 4599-607
[103] Watari J, Takata Y, Ogawa M, Sahara H, Koshino S, Onnela ML, Airaksinen U, Jaatinen R, Penttila M, Keranen S. Molecular cloning and analysis of the yeast flocculation gene FLO1. Yeast. 1994, 10(2): 211-25
[104] Hauser K, Tanner W. Purification of the inducible α-agglutinin of S. cerevisiae and molecular cloning of the gene. FEBS Lett. 1989, 255(2): 290-4
[105] Lipke PN, Chen MH, de Nobel H, Kurjan J, Kahn PC. Homology modeling of an immunoglobulin-like domain in the Saccharomyces cerevisiae adhesion protein α- agglutinin.Protein Sci. 1995, 4(10): 2168-78
[106] Nuoffer C, Jeno P, Conzelmann A, Riezman H. Determinants for glycophospholipid anchoring of the Saccharomyces cerevisiae GAS1 protein to the plasma membrane. Mol Cell Biol. 1991, 11(1): 27-37
[107] Vai M, Gatti E, Lacana E, Popolo L, Alberghina L. Isolation and deduced amino acid sequence of the gene encoding gp115, a yeast glycophospholipid-anchored protein containing a serine-rich region. J Biol Chem. 1991, 266(19): 12242-8
[108] Wilson RB, Davis D, Mitchell AP. Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions.J Bacteriol. 1999, 181(6):1868-74
[109] Loeb JD, Sepulveda-Becerra M, Hazan I, Liu H. A G1 cyclin is necessary for maintenance of filamentous growth in Candida albicans. Mol Cell Biol 1999, 19(6):4019-27
[110] O'Toole G, Kaplan HB, Kolter R. Biofilm formation as microbial development. Annu Rev Microbiol. 2000;54:49-79. Review.