Genetic determinants of p53-induced apoptosis and growth arrest
Genetic determinants of p53-induced apoptosis and growth arrest
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DOI：
10.1101/gad.10.15.1945
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发表时间：
1996-08-01
影响因子：
10.5
通讯作者：
Vogelstein, B
中科院分区：
文献类型：
--
作者：
Polyak, K;Waldman, T;Vogelstein, B
先前的研究表明，p53在癌细胞中的表达可以导致生长停滞或凋亡。因此，p53在一系列结肠直肠癌细胞系中的表达在一些细胞系（A-细胞系）中产生生长停滞，在其他细胞系（D-细胞系）中产生凋亡。为了研究这种差异的基础，我们评估了p21（WAF 1/Cip 1）的作用，这是一种已知的p53诱导生长停滞的介质。通过同源重组使p21失活将A系转化为D系，表明p21可以保护细胞免于凋亡。然而，在自然发生的D系和A系中p53诱导的p21表达的检查表明，p21的诱导不能解释对p53的差异反应。此外，当D系与A系融合时，所得的杂交细胞响应于p53而发生凋亡，表明凋亡途径在生长停滞途径上占主导地位。因此，结肠直肠癌细胞中对p53的凋亡反应受到至少两个因素的调节：p21介导的生长停滞，可以保护A细胞中的细胞免于凋亡，以及D细胞中的反式作用因子，可以克服这种保护，导致细胞死亡。
Previous studies have suggested that expression of p53 in cancer cells can result in either growth arrest or apoptosis. Accordingly, expression of p53 in a series of colorectal cancer cell lines yielded growth arrest in some lines (A-lines) and apoptosis in others (D-lines). To investigate the basis of this difference, we evaluated the role of p21(WAF1/Cip1), a known mediator of p53-induced growth arrest. Inactivation of p21 by homologous recombination converted an A-line to a D-line, suggesting that p21 could protect cells from apoptosis. However, examination of p53-induced p21 expression in naturally occurring D-lines and A-lines demonstrated that the induction of p21 could not account for the differential response to p53. Moreover, when a D-line was fused to an A-line, the resulting hybrid cells underwent apoptosis in response to p53, indicating that the apoptosis pathway was dominant over the growth arrest pathway. Therefore, the apoptotic response to p53 in colorectal cancer cells is modulated by at least two factors: p21-mediated growth arrest that can protect cells from apoptosis in A-cells, and trans-acting factors in D-cells that can overcome this protection, resulting in cell death.