title: Expression of TP53 isoforms p53β or p53γ enhances chemosensitivity in TP53(null) cell lines.
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 p53(null) 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.
authors: Hematology Section, Institute of Medicine, University of Bergen, Bergen, Norway.
authors: Elisabeth
authors: E
authors: Silden
authors: Sigrun M
authors: SM
authors: Hjelle
authors: Line
authors: L
authors: Wergeland
authors: André
authors: A
authors: Sulen
authors: Vibeke
authors: V
authors: Andresen
authors: Jean-Christophe
authors: JC
authors: Bourdon
authors: David R
authors: DR
authors: Micklem
authors: Emmet
authors: E
authors: McCormack
authors: Bjørn Tore
authors: BT
authors: Gjertsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex