Abstract
The carboxy-terminal truncated p53 alternative spliced isoforms, p53β and p53γ, are expressed at disparate levels in cancer and are suggested to influence treatment response and therapy outcome. However, their functional role in cancer remains to be elucidated. We investigated their individual functionality in the p53null background of cell lines H1299 and SAOS-2 by stable retroviral transduction or transient transfection. Expression status of p53β and p53γ protein was found to correlate with increased response to camptothecin and doxorubicin chemotherapy. Decreased DNA synthesis and clonogenicity in p53β and p53γ congenic H1299 was accompanied by increased p21(CIP1/WAF1), Bax and Mdm2 proteins. Chemotherapy induced p53 isoform degradation, most prominent for p53γ. The proteasome inhibitor bortezomib substantially increased basal p53γ protein level, while the level of p53β protein was unaffected. Treatment with dicoumarol, a putative blocker of the proteasome-related NAD(P)H quinone oxidoreductase NQO1, effectively attenuated basal p53γ protein level in spite of bortezomib treatment. Although in vitro proliferation and clonogenicity assays indicated a weak suppressive effect by p53β and p53γ expression, studies of in vivo subcutaneous H1299 tumor growth demonstrated a significantly increased growth by expression of either p53 isoforms. This study suggests that p53β and p53γ share functionality in chemosensitizing and tumor growth enhancement but comprise distinct regulation at the protein level.
Highlights
The gene of the tumor suppressor p53 is shown to encode at least 12 different p53 protein isoforms through alternative splicing, promoter and translational initiation (Figure 1A)
We have previously reported that acute myeloid leukemia patients with high expression of p53b and p53c protein relative to full-length p53 protein respond better to intensive chemotherapy and have a significant longer survival after treatment [6]
Immunoblot analysis demonstrated an upregulation of p21(CIP1/ WAF1) and Bax after exposure to doxorubicin and camptothecin, apparently through a p53-independent mechanism, but with an enhanced p21(CIP1/WAF1) response in p53b+ and p53c+ cells especially in response to camptothecin
Summary
The gene of the tumor suppressor p53 is shown to encode at least 12 different p53 protein isoforms through alternative splicing, promoter and translational initiation (reviewed in [1,2]) (Figure 1A). The differential expression of several of these isoforms has recently been established in cancer, [3,4] though their functional role is not fully understood. Their structural characteristics may indicate isoform specific mechanisms. P53b and p53c is expressed in a tissue-specific manner, which may suggest diverse tissue-determined functions that may be reflected in cancer [5]. This complicates a simple understanding of p53 function, but may support future use of p53 isoform profiles in prediction of outcome and drug sensitivity in cancers
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