The absence of p21(Cip1/WAF1) alters keratinocyte growth and differentiation and promotes ras-tumor progression
The absence of p21(Cip1/WAF1) alters keratinocyte growth and differentiation and promotes ras-tumor progression
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DOI：
10.1101/gad.10.23.3065
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发表时间：
1996-12-01
影响因子：
10.5
通讯作者：
Dotto, GP
中科院分区：
文献类型：
--
作者：
Missero, C;DiCunto, F;Dotto, GP
p21（Cip 1/WAF 1）是第一个被发现的细胞周期蛋白依赖性激酶（cyclin-dependent kinase，CDK）抑制剂，在DNA损伤诱导的细胞生长停滞、细胞衰老和直接CDK调节中起介导作用。p21也可能在分化相关的生长停滞中起重要作用，因为其表达在许多终末分化细胞中增强。p21在生长/分化控制和肿瘤抑制中的一般参与受到质疑，因为缺乏p21的小鼠经历正常发育，在其任何器官中没有明显改变，并且在自发肿瘤发展中没有表现出增加。然而，生长和分化之间的显着不平衡，可以在正常的稳态机制受损的条件下被揭露。我们在这里报告的主要角质形成细胞来源于p21基因敲除小鼠，转化与ras癌基因，并皮下注射到裸鼠表现出非常积极的致瘤行为，这是没有观察到与野生型对照角质形成细胞，也没有与角质形成细胞的破坏密切相关的p27基因。在明确定义的体外条件下测试的p21敲除角质形成细胞显示出显著增加的增殖潜力，这在p27敲除细胞中也观察到，但程度较低。在p21与p27敲除角质形成细胞的分化行为中发现了更深刻的差异，p21（但不是p27）缺陷导致与角质形成细胞终末分化程序的晚期阶段相关的分化标记物的急剧下调。因此，我们的研究结果揭示了一个迄今未被发现的作用，p21在肿瘤抑制，表明这种功能是特定的，因为它不能归因于密切相关的p27分子，并指出一个必不可少的参与p21在终末分化控制，这可能是其在肿瘤抑制的作用。
p21(Cip1/WAF1) was the first cyclin-dependent kinase (CDK) inhibitor to be identified, as a mediator of p53 in DNA damage-induced growth arrest, cell senescence, and direct CDK regulation. p21 may also play an important role in differentiation-associated growth arrest, as its expression is augmented in many terminally differentiating cells. A general involvement of p21 in growth/differentiation control and tumor suppression has been questioned, as mice lacking p21 undergo a normal development, harbor no gross alterations in any of their organs, and exhibit no increase in spontaneous tumor development. However, a significant imbalance between growth and differentiation could be unmasked under conditions where normal homeostatic mechanisms are impaired. We report here that primary keratinocytes derived from p21 knockout mice, transformed with a ras oncogene, and injected subcutaneously into nude mice exhibit a very aggressive tumorigenic behavior, which is not observed with wild-type control keratinocytes nor with keratinocytes with a disruption of the closely related p27 gene. p21 knockout keratinocytes tested under well-defined in vitro conditions show a significantly increased proliferative potential, which is also observed but to a lesser extent with p27 knockout cells. More profound differences were found in the differentiation behavior of p21 versus p27 knockout keratinocytes, with p21 (but not p27) deficiency causing a drastic down-modulation of differentiation markers linked with the late stages of the keratinocyte terminal differentiation program. Thus, our results reveal a so far undetected role of p21 in tumor suppression, demonstrate that this function is specific as it cannot be attributed to the closely related p27 molecule, and point to an essential involvement of p21 in terminal differentiation control, which may account for its role in tumor suppression.