title: Pharmacological blockade of Bcl-2, Bcl-x(L) and Bcl-w by the BH3 mimetic ABT-737 has only minor impact on tumour development in p53-deficient mice.
abstract: The tumour suppressor p53 transcriptionally regulates a range of target genes that control cell growth and survival. Mutations of p53 have been implicated in the development of approximately 50% of human cancers, including those instigated by exposure to mutagens. Although numerically rare, cancers can arise as a consequence of inherited mutations, such as in the Li-Fraumeni syndrome, which is caused by mutation of one p53 allele. Gene-targeted mice deficient for p53 have been generated to study this familial cancer syndrome. On a C57BL/6 background, p53-deficient mice develop primarily thymic lymphoma and more rarely sarcoma. Evasion of apoptosis is considered to be essential for neoplastic transformation. As proteins of the Bcl-2 family are the critical regulators of apoptosis, we investigated the role of the pro-survival members Bcl-2, Bcl-x(L) and Bcl-w in cancer development in p53(+/-) and p53(-/-) mice by testing whether ABT-737, a pharmacological inhibitor of these proteins, could prevent or delay tumourigenesis. Our studies showed that ABT-737 prophylaxis only caused a minor delay and reduction in γ-radiation-induced thymic lymphoma development in p53(-/-) mice, but this was accompanied by a concomitant increase in sarcoma. These data show that, collectively, Bcl-2, Bcl-x(L) and Bcl-w have only minor roles in thymic lymphoma development elicited by defects in p53, and this may indicate that Mcl-1 and/or A1 may feature more prominently in this process.
authors: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors: S
authors: S
authors: Grabow
authors: P
authors: P
authors: Waring
authors: L
authors: L
authors: Happo
authors: M
authors: M
authors: Cook
authors: K D
authors: KD
authors: Mason
authors: P N
authors: PN
authors: Kelly
authors: A
authors: A
authors: Strasser
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides / Q000494:pharmacology*; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; C101155:Bcl2l2 protein, mouse; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein