Induction of p21 and nuclear accumulation of TAp73alpha and c-abl during apoptosis of cisplatin-treated primary pancreatic acinar cells.

To understand the role of endogenous p53 and related proteins in pancreatic injury responses, we established primary pancreatic acinar cultures from wild-type and p53-deficient mice and investigated the relationship between apoptosis, proliferation and underlying molecular events in cells exposed to the DNA cross-linking agent cisplatin. This treatment led to a time-dependent elevation in p53 levels, accompanied by phosphorylation at key serine residues. Despite this apparent activation of p53, acinar cells entered growth arrest unaffected by p53 deficiency. Moreover, p53-null cells exhibited only a temporal delay in engaging apoptosis, compared to wild-type counterparts. Whilst p53-proficient cells rapidly accumulated nuclear p21, the kinetics of p21 accumulation in p53-null cells were delayed, correlating with the execution of p53-independent apoptosis. During the course of treatment, c-abl and TAp73alpha, a p53 homologue, accumulated in acinar cell nuclei, irrespective of genotype, indicating that they are induced upon DNA damage and that they may act in parallel or in concert with p53 for the eradication of damaged acinar cells. We also report the nuclear accumulation of c-abl and TAp73alpha in cells, treated with the nuclear export inhibitor leptomycin B, suggesting that these proteins undergo constant nucleocytoplasmic shuttling in normal culture conditions, possibly reflecting a role for TAp73alpha-mediated transactivation or repression in the regulation of in vitro acinar cell growth.