Resistance to Fas-mediated apoptosis: activation of Caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP

Abstract

The death receptor Fas transduces apoptotic death signaling mediated by caspases. In the present study, human hepatoma HepG2 cells showed the Fas-mediated apoptosis mediated by caspase, especially caspase 3, only in the presence of actinomycin D. Interestingly, cytosolic proteins extracted from intact HepG2 cells induced caspase 3 inactivation. Our results reveal that this inactivation was triggered by the direct inhibition of activated caspase 3 by IAP gene family ILP. In addition, a 53 kDa protein was co-immunoprecipitated with antihuman caspase 3 antibody from intact HepG2 cells. This protein was a complex-protein of procaspase 3 and the cell cycle regulator p21 WAF1 (p21). P21 bound to only procaspase 3, but not to activated caspase 3. We also demonstrate that p21 protein-loaded HepG2 cells resist to Fas-mediated apoptosis even in the presence of actinomycin D. Here we report that caspase 3 inactivation for the resistance to Fas-mediated apoptosis is induced by a procaspase 3/p21 complex formation and direct inhibition of activated caspase 3 by ILP.

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

“…One of the plausible explanations is that antiapoptotic mechanisms such as reduced expression of Fas and expression of antiapoptotic proteins, for example, bcl-2 or XIAP, in addition to survivin or receptormediated survival signals are involved in the progression of antiapoptosis of HCC cells. [29][30][31][32] The findings of both our in vitro and in vivo studies were in good agreement; this confirmed that stable knockdown of survivin abrogated its function in cell cycle regulation, and although it cannot induce spontaneous apoptosis directly and immediately, it sensitizes HCC cells to apoptotic stimuli. Most importantly, our result was consistent with the results of a previous clinical study that survivin expression in HCC tissues strongly correlated with the proliferation index, but did not significantly correlate with the apoptosis index.…”

KLF4, p21 and context-dependent opposing forces in cancer

“…Cytoplasmic p21 can interact with, and thereby inactivate, multiple pro-apoptotic proteins such as SAPK (also known as JNK) 91 , pro-caspase 3 (REF. 92) and ASK1 (apoptosissignal-regulating kinase 1, also known as mitogenactivated protein kinase kinase kinase 5 (MAP3K5)) 93,94 . Cytoplasmic localization of p21 has been reported to correspond with a poor clinical outcome of patients with breast cancer 95,96 , which could therefore be explained by the observation that besides losing its CDK-inhibitory function, cytoplasmic p21 also gains anti-apoptotic functions 93,94 .…”

Macrophage Migration Inhibitory Factor Promotes Cell Death and Aggravates Neurologic Deficits after Experimental Stroke

“…Moreover, it was recently shown that in cultured dermal fibroblasts, the lack of MIF is associated with a reduced nuclear localization of p21 (Taranto et al, 2009), a cyclin-dependent kinase inhibitor (1A) that participates in cell-cycle arrest, suggesting the involvement of MIF in p53-independent mechanisms. Apart from its function in the cell cycle, there is evidence that p21 is a direct inhibitor of apoptosis (Suzuki et al, 1998). Moreover, Harms et al (2007) show that activation of p21 via phosphorylation and translocation into the cytoplasm in neurons prevents apoptosis.…”