Differential effects of p21(WAF1/CIP1) deficiency on MMTV-ras and MMTV-myc mammary tumor properties.
Differential effects of p21(WAF1/CIP1) deficiency on MMTV-ras and MMTV-myc mammary tumor properties.
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发表时间：
2002-04
期刊：
影响因子：
11.2
通讯作者：
D. Bearss;Richard J Lee;D. Troyer;R. Pestell;J. Windle
中科院分区：
文献类型：
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作者：
D. Bearss;Richard J Lee;D. Troyer;R. Pestell;J. Windle
p21(WAF1/CIP1) （p21）作为细胞周期蛋白依赖性激酶（CDK）抑制剂，是p53依赖性生长停滞的关键介质。然而，它在细胞周期调节中的作用是复杂的，因为在某些实验背景下它似乎也促进CDK活性。在与p21（WAF1/CIP1）敲除小鼠（p21-/-）杂交的MMTV-ras和MMTV-myc转基因小鼠中评估了其在肿瘤抑制中的潜在作用。在这两种癌基因存在的情况下，P21缺乏对肿瘤发病率、发病年龄、增殖和凋亡有不同的影响。与MMTV-ras肿瘤相比，MMTV-ras/p21-/-小鼠肿瘤表现出更高的s期分数和相应的细胞周期蛋白D1和E/CDK活性升高。相比之下，MMTV-myc/p21-/-肿瘤的s期分数和细胞周期蛋白D1和E/CDK活性水平低于MMTV-myc肿瘤。在两种肿瘤类型中，细胞周期蛋白D1和E/CDK活性的变化与相应细胞周期蛋白水平的变化是平行的。p21缺乏对两种模型的肿瘤细胞凋亡也有不同的影响。与MMTV-ras肿瘤相比，MMTV-ras/p21-/-肿瘤的自发凋亡显著增加，而p21缺乏对MMTV-myc肿瘤的凋亡影响最小。这些结果表明，p21表达对细胞增殖的影响受到不同癌基因表达的不同影响，p21可能在促进生长阻滞或增殖方面发挥作用，这取决于特定的细胞环境。
p21(WAF1/CIP1) (p21) functions as a cyclin-dependent kinase (CDK) inhibitor and is a key mediator of p53-dependent growth arrest. However, its role in cell cycle regulation is complex, because it also appears to promote CDK activity in certain experimental contexts. Its potential role in tumor suppression was evaluated in MMTV-ras and MMTV-myc transgenic mice that were interbred to p21(WAF1/CIP1) knockout mice (p21-/-). p21 deficiency had differential effects on tumor incidence and age of onset, proliferation, and apoptosis in the presence of these two oncogenes. Tumors arising in MMTV-ras/p21-/- mice displayed higher S-phase fractions and correspondingly increased cyclin D1 and E/CDK activity than MMTV-ras tumors. In contrast, MMTV-myc/p21-/- tumors had lower S-phase fractions and levels of cyclin D1 and E/CDK activity than MMTV-myc tumors. In both tumor types, changes in cyclin D1 and E/CDK activity were paralleled by changes in the corresponding cyclin protein levels. Tumor cell apoptosis was also differentially influenced by p21 deficiency in the two models. MMTV-ras/p21-/- tumors exhibited a significant increase in spontaneous apoptosis as compared with MMTV-ras tumors, whereas p21 deficiency had minimal effect on apoptosis in MMTV-myc tumors. These results indicate that the effects of p21 expression on cellular proliferation are differentially affected by the expression of different oncogenes, and that p21 may play a role in promoting either growth arrest or proliferation, depending on the specific cellular context.