Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype
Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype
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DOI：
10.1074/jbc.m111.257071
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发表时间：
2011-10-21
影响因子：
4.8
通讯作者：
Campisi, Judith
中科院分区：
文献类型：
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作者：
Coppe, Jean-Philippe;Rodier, Francis;Campisi, Judith
细胞衰老通过阻止受到潜在致癌刺激的细胞增殖来抑制癌症。衰老细胞通常表达p16(INK4a)，一种细胞周期蛋白依赖性激酶抑制剂、肿瘤抑制因子和衰老生物标志物，这使得衰老生长停滞不可逆转。衰老细胞还获得复杂的表型，包括许多细胞因子、生长因子和蛋白酶的分泌，称为衰老相关分泌表型（SASP）。 SASP 被认为是与年龄相关的病理学的基础，讽刺的是，其中包括晚年癌症。在这里，我们发现 p16(INK4a) 和另一种细胞周期蛋白依赖性激酶抑制剂 p21(CIP1/WAF1) 的异位表达在没有 SASP 的情况下诱导衰老，尽管它们诱导了衰老的其他特征，包括稳定的生长停滞。此外，通过电离辐射或致癌 RAS 诱导衰老的人类成纤维细胞会产生 SASP，无论它们是否表达 p16(INK4a)。由异位 p16(INK4a) 表达诱导衰老的细胞缺乏上皮细胞的旁分泌活性，这与功能性 SASP 的缺失一致。尽管如此，经历复制性衰老的细胞表达p16(INK4a)限制了DNA损伤的积累和过早细胞因子分泌，表明p16(INK4a)在抑制SASP中具有间接作用。这些发现表明，p16(INK4a)阳性细胞在体内可能并不总是含有SASP，而且，SASP本身并不是p16(INK4a)激活或衰老的结果，而是一种与生长停滞无关的损伤反应。
Cellular senescence suppresses cancer by preventing the proliferation of cells that experience potentially oncogenic stimuli. Senescent cells often express p16(INK4a), a cyclin-dependent kinase inhibitor, tumor suppressor, and biomarker of aging, which renders the senescence growth arrest irreversible. Senescent cells also acquire a complex phenotype that includes the secretion of many cytokines, growth factors, and proteases, termed a senescence-associated secretory phenotype (SASP). The SASP is proposed to underlie age-related pathologies, including, ironically, late life cancer. Here, we show that ectopic expression of p16(INK4a) and another cyclin-dependent kinase inhibitor, p21(CIP1/WAF1), induces senescence without a SASP, even though they induced other features of senescence, including a stable growth arrest. Additionally, human fibroblasts induced to senesce by ionizing radiation or oncogenic RAS developed a SASP regardless of whether they expressed p16(INK4a). Cells induced to senesce by ectopic p16(INK4a) expression lacked paracrine activity on epithelial cells, consistent with the absence of a functional SASP. Nonetheless, expression of p16(INK4a) by cells undergoing replicative senescence limited the accumulation of DNA damage and premature cytokine secretion, suggesting an indirect role for p16(INK4a) in suppressing the SASP. These findings suggest that p16(INK4a)-positive cells may not always harbor a SASP in vivo and, furthermore, that the SASP is not a consequence of p16(INK4a) activation or senescence per se, but rather is a damage response that is separable from the growth arrest.