p21WAF1 Prevents Down-modulation of the Apoptotic Inhibitor Protein c-IAP1 and Inhibits Leukemic Apoptosis

Abstract

Background: Prior studies indicate that leukemias expressing high levels of the p21WAF1 cell cycle inhibitor have a poorer prognosis than p21WAF1negative leukemias. Although p21WAF1 is upregulated by p53 in the setting of DNA damage, the prognostic significance of p21WAF1 is independent of p53 status. The molecular basis of the negative prognostic effect of p21WAF1 remains obscure, but it is believed to result from decreased apoptosis of p21WAF1-expressing leukemias. Materials and Methods: We studied the effects of p21WAF1 on apoptosis of K562 leukemic cells, which lack wild-type p53 and do not express endogenous p21WAF1. An inducible p21WAF1 system was used and the effect of p21WAF1 induction on susceptibility to etoposide-mediated apoptosis was measured. Results: p21WAF1 decreased apoptotic death of K562 leukemic cells in response to etoposide. Analysis of intermediaries in the apoptotic pathway indicated that p21WAF1 had no effect on cytochrome c release or cleavage of procaspase-3. In contrast, p21WAF1 was protective against cleavage of caspase targets poly(ADP-ribose)polymerase (PARP), retinoblastoma protein (Rb), and lamin. The expression of the inhibitor of apoptosis protein c-IAP1, which inhibited the function of executioner caspases 3 and 7, was studied. c-IAP1 protein expression was found to be present in a majority of leukemic blasts from untreated patients, but absent in normal differentiating myeloid progenitor cells. In K562 cells, treatment with etoposide in the absence of p21WAF1 induction resulted in post-transcriptional down-modulation of c-IAP1 levels. c-IAP1 loss involved proteasomal, rather than caspase, degradation pathways. Expression of p21WAF1 sustained c-IAP1 protein levels in the presence of etoposide. Conclusions: Etoposide-mediated apoptosis involves down-modulation of the anti-apoptotic protein c-IAP1. Our findings support the hypothesis that p21WAF1 contributes to leukemic chemoresistance by stabilizing c-IAP1 levels in the presence of chemotherapy.

Distribution of Neuronal Apoptosis Inhibitory Protein in Human Tissues

“…It could be the case that (among other factors) the expression of p21 WAF1 , and the subsequent withdrawal from the cell cycle, triggers NAIP expression. A connection between IAPs, p21 WAF1 , and apoptosis regulation has been previously reported (Suzuki et al 1998;Suzuki et al 2000a;Steinman and Johnson 2000). The regulator protein p21…”

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

“…p21 plays an essential role in growth arrest after DNA damage (27)(28)(29) and overexpression leads to G 1 and G 2 or S-phase arrest (30,31). It has been reported that p21 interaction with procaspase 3 leads to resistance to Fas-mediated cell death, and stabilization of the apoptotic inhibitor protein c-IAP1 (32,33). Overexpression of p21 completely blocked DR4 TRIL receptor cytoplasmic domain (CD)-induced cleavage of caspase-8 and DR4-CD-induced apoptosis, and this activity resides within 91 amino acids of the NH 2 terminus of p21 protein (34).…”

Concomitant Inhibition of MDM2 and Bcl-2 Protein Function Synergistically Induce Mitochondrial Apoptosis in AML

“…37 The mechanisms by which p21 inhibits cell death include inhibition of caspase-8 cleavage, 38 interaction with procaspase-3 masking the serine proteinase-cleaving site, 39 and stabilization of the apoptotic inhibitor protein c-IAP1. 40 It is therefore likely that the cell cycle-dependent expression of p21 is closely associated with cell susceptibility to p53-dependent apoptosis.…”