p21(Waf1/Cip1) protects against p53-mediated apoptosis of human melanoma cells
p21(Waf1/Cip1) protects against p53-mediated apoptosis of human melanoma cells
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DOI：
10.1038/sj.onc.1200897
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发表时间：
1997-02-27
期刊：
影响因子：
8
通讯作者：
Holbrook, NJ
中科院分区：
文献类型：
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作者：
Gorospe, M;Cirielli, C;Holbrook, NJ
p53的肿瘤抑制作用被认为源于其两个主要功能：实施细胞生长停滞和执行凋亡性细胞死亡，而p53调节细胞周期蛋白依赖性激酶抑制剂p21的表达（Waf 1/Cip 1）似乎是实施G（1）逮捕的核心，P21的参与在本研究中，通过使用腺病毒表达载体在人黑色素瘤SK-MEL-110细胞中过表达p53，发现AdCMV，p53的感染导致细胞凋亡，而类似的原代血管平滑肌细胞（VSMC）的感染反而导致生长的中度抑制。（Waf 1/Cip 1）在VSMC中显著升高，但在SK-MEL-110细胞中几乎没有变化，尽管另一种p53调节基因（GADD 45）的表达在两种AdCMV.p53感染的细胞类型中相当，证据表明，p21 p53过表达对p21-Cip 1高毒性的发现进一步支持了Waf 1/Cip 1表达可能是p53诱导的细胞死亡存活所必需的。在SK-MEL-110和p21（-/-）MEFs中，腺病毒驱动的p21（Waf 1/Cip 1）的异位表达导致对p53诱导的凋亡的实质性保护，表明p21（Waf 1/Cip 1）将细胞从程序性细胞死亡的路径拯救到增强的存活的路径。
The tumor suppressive effect of p53 is believed to be rooted in its two primary functions: the implementation of cellular growth arrest and the execution of apoptotic cell death, While p53-regulated expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) appears to be central for the implementation of G(1) arrest, the participation of p21(Waf1/Cip1) in p53-triggered cell death remains controversial, In the present study, overexpression of p53 in human melanoma SK-MEL-110 cells through use of an adenoviral expression vector (AdCMV,p53) was found to result in apoptosis, while similar infection of primary vascular smooth muscle cells (VSMC) instead resulted in a moderate inhibition of growth, Expression of p21(Waf1/Cip1) was strongly elevated in VSMC, but showed little change in SK-MEL-110 cells, although expression of another p53-regulated gene (GADD45) was comparable in both AdCMV.p53-infected cell types, Evidence that p21(Waf1/Cip1) expression may be required for surviving p53-induced cell death was further supported by the finding that p53 overexpression was highly toxic for p21-deficient mouse embryonal fibroblasts (p21(-/-) MEFs), In both SK-MEL-110 and p21(-/-) MEFs, adenovirus-driven ectopic expression of p21(Waf1/Cip1) resulted in a substantial protection against p53-induced apoptosis, indicating that p21(Waf1/Cip1) rescued cells from a path of programmed cell death to one of enhanced survival.