p21 promotes ceramide-induced apoptosis and antagonizes the antideath effect of Bcl-2 in human hepatocarcinoma cells
p21 promotes ceramide-induced apoptosis and antagonizes the antideath effect of Bcl-2 in human hepatocarcinoma cells
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DOI：
10.1006/excr.1999.4644
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发表时间：
1999-12-15
影响因子：
3.7
通讯作者：
Choi, KH
中科院分区：
文献类型：
--
作者：
Kang, KH;Kim, WH;Choi, KH
p21 是一种有效的细胞周期蛋白依赖性激酶抑制剂，已知可诱导细胞周期停滞以响应 DNA 损伤剂。尽管p21已被报道在细胞凋亡调节中发挥重要作用，但p21在细胞凋亡中的假定作用仍然存在争议。此前，我们报道了在神经酰胺诱导的人肝癌细胞系细胞凋亡过程中，pal 以不依赖于 p53 的方式被诱导。在本研究中，我们通过使用四环素诱导表达系统研究了 p21 在神经酰胺诱导的人肝癌细胞凋亡中的精确作用。 pal 本身的过表达不会诱导 p53 缺陷的 Hep3B 细胞凋亡。然而，Hep3B/p21 细胞对神经酰胺诱导的细胞凋亡更敏感。在这些细胞中，p21 过度表达不会导致 G1 期停滞。在用神经酰胺处理的Hep3B/p21细胞中，Pax的表达水平增加，并且与p21抑制条件相比，在p21过表达条件下其表达更加加速。 Bax 的过度表达诱导 Hep3B 细胞凋亡。另一方面，在另一种肝癌细胞系SK-Hep-1中，神经酰胺增加了pal和Bax蛋白的水平，而Bcl-2蛋白水平没有改变。 Bcl-2的过度表达不仅抑制细胞凋亡，而且完全阻止SK-Hep-1细胞中神经酰胺引起的p21和Bax的诱导。此外，p21的过度表达会拮抗Bcl-2的死亡保护功能并上调Bax蛋白的表达。这些结果表明，p21 通过增强 Pax 的表达来促进神经酰胺诱导的细胞凋亡，从而调节人肝癌细胞中 Bcl-2:Bax 的分子比率，(C) 1999 年学术出版社。
p21, a potent cyclin-dependent kinase inhibitor, has been known to induce cell cycle arrest in response to DNA-damaging agents. Although p21 has been reported to play an important role in the regulation of apoptosis, the postulated role for p21 in apoptosis is still controversial. Previously, we reported that pal was induced in a p53-independent manner during ceramide-induced apoptosis in human hepatocarcinoma cell lines. In the present study, we investigated the precise role of p21 in ceramide-induced apoptosis in human hepatocarcinoma cells by using a tetracycline-inducible expression system. Overexpression of pal by itself did not induce apoptosis in p53-deficient Hep3B cells. However, Hep3B/p21 cells were more sensitive to ceramide-induced apoptosis. In these cells, p21 overexpression did not result in G1 arrest. The expression level of Pax was increased in Hep3B/p21 cells treated with ceramide and its expression was more accelerated under the p21-overexpressed condition compared to that of the p21-repressed condition. Overexpression of Bax induced apoptosis in Hep3B cells. On the other hand, the levels of pal and Bax protein were increased by ceramide in another hepatocarcinoma cell line, SK-Hep-1, while the Bcl-2 protein level was not changed. Overexpression of Bcl-2 not only suppressed apoptosis but also completely prevented induction of p21 and Bax caused by ceramide in SK-Hep-l cells. Furthermore, overexpression of p21 antagonized the death-protective function of Bcl-2 and upregulated expression of Bax protein. These results suggest that p21 promotes ceramide-induced apoptosis by enhancing the expression of Pax, thereby modulating the molecular ratio of Bcl-2:Bax in human hepatocarcinoma cells, (C) 1999 Academic Press.