Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression:: Implications for carcinogenesis, senescence, and age-related diseases
Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression:: Implications for carcinogenesis, senescence, and age-related diseases
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DOI：
10.1073/pnas.97.8.4291
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发表时间：
2000-04-11
影响因子：
11.1
通讯作者：
Roninson, IB
中科院分区：
文献类型：
--
作者：
Chang, BD;Watanabe, K;Roninson, IB
细胞周期蛋白依赖性激酶抑制剂p21（Waf1/Cip1/Sdi1）的诱导可触发与衰老和损伤反应相关的细胞生长停滞。人类细胞系中诱导启动子p21的过度表达可引起生长停滞和衰老的表型特征。cDNA阵列杂交显示，p21的表达选择性地抑制了一组参与有丝分裂、DNA复制、分离和修复的基因。这些基因对p21诱导的抑制动力学与生长停滞的开始相似，它们在p21释放时的重新表达在细胞重新进入细胞周期之前，表明细胞周期进展基因的抑制是p21诱导生长停滞的一种机制，p21还上调了与衰老相关的多个基因，或与年龄相关的疾病有关，包括动脉粥样硬化、阿尔茨海默病、淀粉样变性和关节炎。大多数测试的p21诱导的基因在被血清饥饿抑制生长的细胞中没有被激活，但一些基因在两种形式的生长抑制中都被诱导。一些p21诱导的基因编码对细胞生长和凋亡具有旁分泌作用的分泌蛋白，与这些蛋白的过度表达一致，p21诱导细胞的条件培养基具有抗凋亡和有丝分裂活性。这些结果表明，p21诱导衰老细胞基因表达的作用可能有助于癌症和年龄相关疾病的发病机制。
Induction of cyclin-dependent kinase inhibitor p21(Waf1/Cip1/Sdi1) triggers cell growth arrest associated with senescence and damage response. Overexpression of p21 from an inducible promoter in a human cell line induces growth arrest and phenotypic features of senescence. cDNA array hybridization showed that p21 expression selectively inhibits a set of genes involved in mitosis, DNA replication, segregation, and repair. The kinetics of inhibition of these genes on p21 induction parallels the onset of growth arrest, and their reexpression on release from p21 precedes the reentry of cells into cell cycle, indicating that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest, p21 also up-regulates multiple genes that have been associated with senescence or implicated in age-related diseases, including atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis, Most of the tested p21-induced genes were not activated in cells that had been growth arrested by serum starvation, but some genes were induced in both forms of growth arrest. Several p21-induced genes encode secreted proteins with paracrine effects on cell growth and apoptosis, In agreement with the overexpression of such proteins, conditioned media from p21-induced cells were found to have antiapoptotic and mitogenic activity. These results suggest that the effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.