Notch1基因对人胶质瘤U251细胞增殖和周期的影响及其机制的初步研究
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摘要
目的:
1、检测Notch1基因对人胶质瘤U251增殖和细胞周期的影响。
2、探讨Notch1基因影响人胶质瘤U251细胞增殖和周期的可能机制。
方法:
1、利用Notch1-shRNA和pNL-NICD/EGFP慢病毒感染人胶质瘤U251细胞,RT-PCR和Western Blotting法筛选和鉴定Notch1表达下调或Notch1胞内段(Notch1 intracellular domain, NICD)表达上调的U251细胞。
2、MTT法和PI单染流式细胞术分析Notch1对细胞增殖和细胞周期的影响。
3、采用RT-PCR和Western blotting法检测NF-κB p65表达;EMSA法检测NF-κB的活性。
4、采用RT-PCR法检测细胞周期相关基因,包括p53, p21, p27, p16, cyclinD1, cyclinE1, cyclinA2, cyclinB1, cyclinB2, CDK2, CDK4, CDK6, Cdc25C的表达情况,对mRNA表达水平变化的基因,进一步采用Western blotting法检测其蛋白表达水平。
结果:
1、Notch1-shRNA慢病毒表达载体能有效下调U251细胞Notch1的表达,而pNL-NICD/EGFP慢病毒表达载体能有效上调U251细胞NICD的表达。
2、Notch1基因表达下调的细胞其细胞增殖能力受到明显抑制(P<0.01),并引起细胞G1期阻滞(P<0.01), S期细胞减少(P<0.01);在NICD表达上调的细胞其增殖能力明显增强(P<0.01),且引起G1期细胞减少(P<0.05),S期细胞增加(P<0.01)。
3、Notch1基因表达下调的细胞其NF-κB p65 mRNA和蛋白表达水平显著降低(P<0.05),NF-κB DNA结合活性显著降低(P<0.01);在NICD表达上调的细胞其NF-κB p65mRNA和蛋白表达水平显著增加(P<0.01),NF-κB DNA结合活性显著增加(P<0.01)。
4、Notch1基因表达下调的细胞其cyclinD1、cyclinA2、CDK2、Cdc25C的mRNA和蛋白表达水平显著降低(P<0.01);而在NICD表达上调的细胞,这些基因的mRNA和蛋白表达水平显著增加(P<0.05)。
结论:
1、Notch1基因与人胶质瘤U251细胞的增殖能力和周期调控密切相关。
2、Notch1基因可能通过NF-κB通路影响U251细胞的增殖,且可能部分通过NF-κB p65起作用。
3、Notch1基因可通过cyclinD1、cyclinA2、CDK2和Cdc25C影响U251细胞的周期进程。
Objective:
1、To investigate the effect of Notch1 gene on the change of proliferation and cell cycle in human glioma U251 cell.
2、To research the possible mechanisms of Notch1 gene involved in proliferation and cell cycle in human glioma U251 cell.
Methods:
1、The lentiviral vectors, which expressed Notch1 shRNA or Notch1 intracellular domain (NICD), were transfected into U251 cell respectively. RT-PCR and Western Blotting were applied to monitor the validity of down-regulation of Notch1 expression and over-expression of NICD.
2、MTT assay was performed to examine the cell proliferation. Flow cytometric analysis was used to detect the cell cycle.
3、RT-PCR and Western Blotting were applied to monitor the expression of NF-κB p65. EMSA was performed to assay the NF-κB DNA-binding activity.
4、RT-PCR was applied to monitor the expression of capital genes involved in cell cycle, which included p53, p21 , p27 , p16, cyclinD1, cyclinE1, cyclinA2, cyclinB1, cyclinB2, CDK2, CDK4, CDK6, Cdc25C. Then Western Blot was used to check the genes changed in mRNA expression.
Results:
1、The lentiviral vectors, which expressed Notch1 shRNA or NICD, were efficient in down-regulation of Notch1 expression and over-expression of NICD respectively.
2、Down-regulation of Notch1 gene by RNAi inhibited cell proliferation remarkably(P<0.01), arrested cell cycle at G1 phase (P<0.01) and decreased the cell number of S phase(P<0.01). Over-expression of NICD enhanced the cell proliferation significantly (P<0.01), promoted cell cycle at G1 phase (P<0.05) and increased the cell number of S phase (P<0.01).
3、Down-regulation of Notch1 gene by RNAi inhibited NF-κB p65 expression(P<0.05) and decreased NF-κB DNA-binding activity(P<0.01). Over-expression of NICD enhanced NF-κB p65 expression (P<0.01) and increased NF-κB DNA-binding activity (P<0.01) in U251 cell.
4、Down-regulation of Notch1 gene by RNAi inhibited the expression of cyclinD1, cyclinA2 and Cdc25C (P<0.05). Over-expression of NICD enhanced the expression of cyclinD1, cyclinA2, CDK2 and Cdc25C (P<0.05) in U251 cells.
Conclusion:
1、Notch1 gene leads to the change of proliferation and cell cycle in human glioma U251 cell.
2、Notch1 gene mybe enhance the cell proliferation via increasing NF-κB DNA-binding activity and which may be dependent on increasing the expression of NF-κB p65 partially in U251 cell.
3、Notch1 gene maybe enhance the cell cycle via increasing the expression of cyclinD1, cyclinA2, CDK2 and Cdc25C in U251 cell.
1、检测Notch1基因对人胶质瘤U251增殖和细胞周期的影响。
2、探讨Notch1基因影响人胶质瘤U251细胞增殖和周期的可能机制。
方法:
1、利用Notch1-shRNA和pNL-NICD/EGFP慢病毒感染人胶质瘤U251细胞,RT-PCR和Western Blotting法筛选和鉴定Notch1表达下调或Notch1胞内段(Notch1 intracellular domain, NICD)表达上调的U251细胞。
2、MTT法和PI单染流式细胞术分析Notch1对细胞增殖和细胞周期的影响。
3、采用RT-PCR和Western blotting法检测NF-κB p65表达;EMSA法检测NF-κB的活性。
4、采用RT-PCR法检测细胞周期相关基因,包括p53, p21, p27, p16, cyclinD1, cyclinE1, cyclinA2, cyclinB1, cyclinB2, CDK2, CDK4, CDK6, Cdc25C的表达情况,对mRNA表达水平变化的基因,进一步采用Western blotting法检测其蛋白表达水平。
结果:
1、Notch1-shRNA慢病毒表达载体能有效下调U251细胞Notch1的表达,而pNL-NICD/EGFP慢病毒表达载体能有效上调U251细胞NICD的表达。
2、Notch1基因表达下调的细胞其细胞增殖能力受到明显抑制(P<0.01),并引起细胞G1期阻滞(P<0.01), S期细胞减少(P<0.01);在NICD表达上调的细胞其增殖能力明显增强(P<0.01),且引起G1期细胞减少(P<0.05),S期细胞增加(P<0.01)。
3、Notch1基因表达下调的细胞其NF-κB p65 mRNA和蛋白表达水平显著降低(P<0.05),NF-κB DNA结合活性显著降低(P<0.01);在NICD表达上调的细胞其NF-κB p65mRNA和蛋白表达水平显著增加(P<0.01),NF-κB DNA结合活性显著增加(P<0.01)。
4、Notch1基因表达下调的细胞其cyclinD1、cyclinA2、CDK2、Cdc25C的mRNA和蛋白表达水平显著降低(P<0.01);而在NICD表达上调的细胞,这些基因的mRNA和蛋白表达水平显著增加(P<0.05)。
结论:
1、Notch1基因与人胶质瘤U251细胞的增殖能力和周期调控密切相关。
2、Notch1基因可能通过NF-κB通路影响U251细胞的增殖,且可能部分通过NF-κB p65起作用。
3、Notch1基因可通过cyclinD1、cyclinA2、CDK2和Cdc25C影响U251细胞的周期进程。
Objective:
1、To investigate the effect of Notch1 gene on the change of proliferation and cell cycle in human glioma U251 cell.
2、To research the possible mechanisms of Notch1 gene involved in proliferation and cell cycle in human glioma U251 cell.
Methods:
1、The lentiviral vectors, which expressed Notch1 shRNA or Notch1 intracellular domain (NICD), were transfected into U251 cell respectively. RT-PCR and Western Blotting were applied to monitor the validity of down-regulation of Notch1 expression and over-expression of NICD.
2、MTT assay was performed to examine the cell proliferation. Flow cytometric analysis was used to detect the cell cycle.
3、RT-PCR and Western Blotting were applied to monitor the expression of NF-κB p65. EMSA was performed to assay the NF-κB DNA-binding activity.
4、RT-PCR was applied to monitor the expression of capital genes involved in cell cycle, which included p53, p21 , p27 , p16, cyclinD1, cyclinE1, cyclinA2, cyclinB1, cyclinB2, CDK2, CDK4, CDK6, Cdc25C. Then Western Blot was used to check the genes changed in mRNA expression.
Results:
1、The lentiviral vectors, which expressed Notch1 shRNA or NICD, were efficient in down-regulation of Notch1 expression and over-expression of NICD respectively.
2、Down-regulation of Notch1 gene by RNAi inhibited cell proliferation remarkably(P<0.01), arrested cell cycle at G1 phase (P<0.01) and decreased the cell number of S phase(P<0.01). Over-expression of NICD enhanced the cell proliferation significantly (P<0.01), promoted cell cycle at G1 phase (P<0.05) and increased the cell number of S phase (P<0.01).
3、Down-regulation of Notch1 gene by RNAi inhibited NF-κB p65 expression(P<0.05) and decreased NF-κB DNA-binding activity(P<0.01). Over-expression of NICD enhanced NF-κB p65 expression (P<0.01) and increased NF-κB DNA-binding activity (P<0.01) in U251 cell.
4、Down-regulation of Notch1 gene by RNAi inhibited the expression of cyclinD1, cyclinA2 and Cdc25C (P<0.05). Over-expression of NICD enhanced the expression of cyclinD1, cyclinA2, CDK2 and Cdc25C (P<0.05) in U251 cells.
Conclusion:
1、Notch1 gene leads to the change of proliferation and cell cycle in human glioma U251 cell.
2、Notch1 gene mybe enhance the cell proliferation via increasing NF-κB DNA-binding activity and which may be dependent on increasing the expression of NF-κB p65 partially in U251 cell.
3、Notch1 gene maybe enhance the cell cycle via increasing the expression of cyclinD1, cyclinA2, CDK2 and Cdc25C in U251 cell.
引文
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[1] Morgan TH, Bridges CB. Sex-linked inheritance in Drosophila[M]. Number 237. Washington: Carnegie Institution of Washington publication, 1916, 1–88.
[2] Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats [J]. Cell, 1985, 43(3 Pt 2): 567-581.
[3] Fiúza UM, Arias AM. Cell and molecular biology of Notch[J]. J Endocrinol, 2007, 194(3):459-474.
[4] Koch U, Radtke F. Notch and cancer: a double-edged sword[J]. Cell MolLife Sci, 2007, 64(21):2746–2762.
[5] Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling——a structural and biochemical perspective[J]. J Cell Sci, 2008, 121(19):3109-3119.
[6] Miele L. Notch signaling [J]. Clin Cancer Res, 2006, 12(4):1074 -1079.
[7] Kopan R. Notch: A membrane-bound transcription factor [J]. J Cell Sci, 2002, 115 (6): 1095-1097.
[8] D'Souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands[J]. Oncogene, 2008, 27(38):5148-5167.
[9] Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin- metalloprotease TACE[J]. Mol Cell, 2000, 5(2):207-216.
[10] Okochi M, Steiner H, Fukumori A, et al. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1[J]. EMBO J, 2002, 21(20):5408-5416.
[11] Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes[J]. Cell Mol Life Sci, 2009, 66(10):1631-1646.
[12]李斌,甄海宁,章翔. Notch信号在中枢神经系统肿瘤中的研究进展[J].第四军医大学学报, 2008, 29(2):184-186.
[13]王霞,李萍.细胞周期调控与肿瘤研究进展[J].中国医学检验杂志, 2006,7(1):59-61.
[14]冯作化,药立波,周春燕等.医学分子生物学[M].第1版.北京:人民卫生出版社, 2005, 1:145-150.
[15] Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond[J]. Dev Cell, 2008, 14(2):159-169.
[16] Farley J, Ozbun L, Samimi G, et al. Cell cycle and related protein[J]. Dis Markers, 2007, 23(5-6):433-443.
[17] Pietenpol JA, Stewart ZA. Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis[J]. Toxicology, 2002, 181-182:475-481.
[18] Golias CH, Charalabopoulos A, Charalabopoulos K. Cell proliferation and cell cycle control: a mini review[J]. Int J Clin Pract, 2004, 58(12):1134-1141.
[19] Giacinti C, Giordano A. RB and cell cycle progression[J]. Oncogene, 2006, 25(38):5220-5227.
[20] Sánchez I, Dynlacht BD. New insights into cyclins, CDKs, and cell cycle control[J]. Semin Cell Dev Biol, 2005, 16(3):311-321.
[21] Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm[J]. Nat Rev Cancer, 2009, 9(3):153-166.
[22] Liu JH, Wei S, Burnette PK, et al. Functional association of TGF-beta receptor II with cyclin B[J]. Oncogene, 1999, 18(1): 269-275.
[23] Lewis HD, Leveridge M, Strack PR, et al. Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of Notch signaling[J]. Chem Biol, 2007, 14(2):209-219.
[24] Palomero T, Barnes KC, Real PJ, et al. CUTLL1, a novel human T-cell lymphoma cell with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors[J]. Leukemia, 2006, 20(7):1279-1287.
[25] Guo D, Ye J, Dai J, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cells[J]. Leuk Res, 2009, 33(5):678-685.
[26] Xu P, Qiu M, Zhang Z, et al. The oncogenic roles of Notch1 in astrocytic gliomas in vitro and in vivo[J]. J Neurooncol, 2010, 97(1):41-51.
[27] Wang Z, Zhang Y, Li Y, et al. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancercells[J]. Mol Cancer Ther, 2006, 5(3):483-493.
[28] Wang Z, Banerjee S, Li Y, et al. Down-regulation of Notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells[J]. Cancer Res, 2006, 66(5):2778-2784.
[29] Sj?lund J, Johansson M, Manna S, et al. Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo[J]. J Clin Invest, 2008, 118(1):217-228.
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[31] Talora C, Cialfi S, Segatto O, et al. Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways[J]. Exp Cell Res, 2005, 305(2):343-354.
[32] Yao J, Duan L, Fan M, et al. Notch1 induces cell cycle arrest and apoptosis in human cervical cancer cells: involvement of nuclear factor kappa B inhibition[J]. Int J Gynecol Cancer, 2007, 17(2):502-510.
[33] Wang L, Qin H, Chen B, et al. Overexpressed active Notch1 induces cell growth arrest of HeLa cervical carcinoma cells[J]. Int J Gynecol Cancer, 2007, 17(6):1283-1292.
[34] Sriuranpong V, Borges MW, Ravi RK, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells[J]. Cancer Res, 2001, 61(7):3200-3205.
[35] Qi R, An H, Yu Y, et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis[J]. Cancer Res, 2003, 63(23):8323-8329.
[36] Duan L, Yao J, Wu X, et al. Growth suppression induced by Notch1 activation involves Wnt-beta-catenin down-regulation in humantongue carcinoma cells[J]. Biol Cell, 2006, 98(8):479-490.
[37] Lu Z, Liu H, Xue L, et al. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell EC9706[J]. Int J Oncol, 2008, 32(3):643-651.
[38] Rao SS, O'Neil J, Liberator CD, et al.Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells[J]. Cancer Res, 2009, 69(7):3060-3068.
[39] Ronchini C, Capobianco AJ. Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic)[J]. Mol Cell Biol, 2001, 21(17):5925- 5934.
[40] Morimura T, Goitsuka R, Zhang Y, et al. Cell cycle arrest and apoptosis induced by Notch1 in B cells[J]. J Biol Chem, 2000, 275(47):36523-36531.
[2] Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats [J]. Cell, 1985, 43(3 Pt 2): 567-581.
[3] Fiúza UM, Arias AM. Cell and molecular biology of Notch[J]. J Endocrinol, 2007, 194(3):459-474.
[4] Koch U, Radtke F. Notch and cancer: a double-edged sword[J]. Cell Mol Life Sci, 2007, 64(21):2746–2762.
[5] Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes[J]. Cell Mol Life Sci, 2009, 66(10):1631-1646.
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[64] Giacinti C, Giordano A. RB and cell cycle progression[J]. Oncogene, 2006, 25(38):5220-5227.
[65] Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm[J]. Nat Rev Cancer, 2009, 9(3):153-166.
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[71] Sj?lund J, Johansson M, Manna S, et al. Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo[J]. J Clin Invest, 2008, 118(1):217-228.
[72] Talora C, Cialfi S, Segatto O, et al. Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways[J]. Exp Cell Res, 2005, 305(2):343-354.
[73] Sriuranpong V, Borges MW, Ravi RK, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells[J]. Cancer Res, 2001, 61(7):3200-3205.
[74] Qi R, An H, Yu Y, et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis[J]. Cancer Res, 2003, 63(23):8323-8329.
[75] Duan L, Yao J, Wu X, et al. Growth suppression induced by Notch1 activation involves Wnt-beta-catenin down-regulation in humantongue carcinoma cells[J]. Biol Cell, 2006, 98(8):479-490.
[76] Lu Z, Liu H, Xue L, et al. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell EC9706[J]. Int J Oncol, 2008, 32(3):643-651.
[77] Rao SS, O'Neil J, Liberator CD, et al. Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells[J]. Cancer Res, 2009, 69(7):3060-3068.
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[79] Morimura T, Goitsuka R, Zhang Y, et al. Cell cycle arrest and apoptosis induced by Notch1 in B cells[J]. J Biol Chem, 2000, 275(47):36523-36531.
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[1] Morgan TH, Bridges CB. Sex-linked inheritance in Drosophila[M]. Number 237. Washington: Carnegie Institution of Washington publication, 1916, 1–88.
[2] Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats [J]. Cell, 1985, 43(3 Pt 2): 567-581.
[3] Fiúza UM, Arias AM. Cell and molecular biology of Notch[J]. J Endocrinol, 2007, 194(3):459-474.
[4] Koch U, Radtke F. Notch and cancer: a double-edged sword[J]. Cell MolLife Sci, 2007, 64(21):2746–2762.
[5] Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling——a structural and biochemical perspective[J]. J Cell Sci, 2008, 121(19):3109-3119.
[6] Miele L. Notch signaling [J]. Clin Cancer Res, 2006, 12(4):1074 -1079.
[7] Kopan R. Notch: A membrane-bound transcription factor [J]. J Cell Sci, 2002, 115 (6): 1095-1097.
[8] D'Souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands[J]. Oncogene, 2008, 27(38):5148-5167.
[9] Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin- metalloprotease TACE[J]. Mol Cell, 2000, 5(2):207-216.
[10] Okochi M, Steiner H, Fukumori A, et al. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1[J]. EMBO J, 2002, 21(20):5408-5416.
[11] Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes[J]. Cell Mol Life Sci, 2009, 66(10):1631-1646.
[12]李斌,甄海宁,章翔. Notch信号在中枢神经系统肿瘤中的研究进展[J].第四军医大学学报, 2008, 29(2):184-186.
[13]王霞,李萍.细胞周期调控与肿瘤研究进展[J].中国医学检验杂志, 2006,7(1):59-61.
[14]冯作化,药立波,周春燕等.医学分子生物学[M].第1版.北京:人民卫生出版社, 2005, 1:145-150.
[15] Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond[J]. Dev Cell, 2008, 14(2):159-169.
[16] Farley J, Ozbun L, Samimi G, et al. Cell cycle and related protein[J]. Dis Markers, 2007, 23(5-6):433-443.
[17] Pietenpol JA, Stewart ZA. Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis[J]. Toxicology, 2002, 181-182:475-481.
[18] Golias CH, Charalabopoulos A, Charalabopoulos K. Cell proliferation and cell cycle control: a mini review[J]. Int J Clin Pract, 2004, 58(12):1134-1141.
[19] Giacinti C, Giordano A. RB and cell cycle progression[J]. Oncogene, 2006, 25(38):5220-5227.
[20] Sánchez I, Dynlacht BD. New insights into cyclins, CDKs, and cell cycle control[J]. Semin Cell Dev Biol, 2005, 16(3):311-321.
[21] Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm[J]. Nat Rev Cancer, 2009, 9(3):153-166.
[22] Liu JH, Wei S, Burnette PK, et al. Functional association of TGF-beta receptor II with cyclin B[J]. Oncogene, 1999, 18(1): 269-275.
[23] Lewis HD, Leveridge M, Strack PR, et al. Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of Notch signaling[J]. Chem Biol, 2007, 14(2):209-219.
[24] Palomero T, Barnes KC, Real PJ, et al. CUTLL1, a novel human T-cell lymphoma cell with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors[J]. Leukemia, 2006, 20(7):1279-1287.
[25] Guo D, Ye J, Dai J, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cells[J]. Leuk Res, 2009, 33(5):678-685.
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