title: BCR/ABL recruits p53 tumor suppressor protein to induce drug resistance.
abstract: Tumors expressing the ABL oncoproteins (BCR/ABL, TEL/ABL, v-ABL) can avoid apoptosis triggered by DNA damaging agents. The tumor suppressor protein p53 is an important activator of apoptosis in normal cells; conversely its functional loss may cause drug resistance. The ABL oncoprotein-p53 paradigm represents the relationship between an oncogenic tyrosine kinase and a tumor suppressor gene. Here we show that BCR/ABL oncoproteins employ p53 to induce resistance to DNA damage in myeloid leukemia cells. Cells transformed by the ABL oncoproteins displayed accumulation of p53 upon DNA damage. In contrast, only a modest increase of p53 expression followed by activation of caspase-3 were detected in normal cells expressing endogenous c-ABL. Phosphatidylinositol-3 kinase-like protein kinases (ATR and also ATM) -dependent phosphorylation of p53-Ser15 residue was associated with the accumulation of p53, and stimulation of p21(Waf-1) and GADD45, resulting in G(2)/M delay in BCR/ABL cells after genotoxic treatment. Inhibition of p53 by siRNA or by the temperature-sensitive mutation reduced G(2)/M accumulation and drug resistance of BCR/ABL cells. In conclusion, accumulation of the p53 protein contributed to prolonged G(2)/M checkpoint activation and drug resistance in myeloid cells expressing the BCR/ABL oncoproteins.
authors.affiliation: Molecular Carcinogenesis Section, Center of Biotechnology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, Pennsylvania 19122, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: Artur
authors.initials: A
authors.lastname: Slupianek
authors.forename: Mandrita
authors.initials: M
authors.lastname: Datta
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Michal O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: Mateusz
authors.initials: M
authors.lastname: Koptyra
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D051379:Mice; D008957:Models, Genetic; D009153:Mutagens / Q000633:toxicity; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D009153:Mutagens; D016374:Oncogene Proteins v-abl; D016159:Tumor Suppressor Protein p53; D008769:Methylnitronitrosoguanidine; D004247:DNA; D016044:Fusion Proteins, bcr-abl