title: p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma.
abstract: The effect of Bcl-2 on oncogenesis is complex and expression may either delay or accelerate oncogenesis. The pro-oncogenic activity is attributed to its well characterized anti-apoptotic function while the anti-oncogenic function has been attributed to its inhibition of cellular proliferation. Recent studies demonstrate that p27 may mediate the effects of Bcl-2 on cellular proliferation. We hypothesized that p27 may suppress tumor formation by Bcl-2 family members. To test this hypothesis, cell cycle inhibition and lymphoma development were examined in Lck-Bcl-2 and Lck-Bax38/1 transgenic mice deficient in p27. Strikingly, p27 deficiency synergistically cooperates with Bcl-2 to increase T cell hyperplasia and development of spontaneous T cell lymphomas. Within 1 year, >90% of these mice had developed thymic T cell lymphomas. This high penetrance contrasts with a one year incidence of <5% of thymic lymphoma in Lck-Bcl-2 or p27 -/- mice alone. In contrast, p27 deficiency had no effect on tumor formation in Lck-Bax38/1 transgenic mice, another model of T cell lymphoma. Histologically the lymphomas in p27 -/- Lck-Bcl-2 mice are lymphoblastic and frequently involve multiple organs suggesting an aggressive phenotype. Interestingly, in mature splenic T cells, Bcl-2 largely retains its anti-proliferative function even in the absence of p27. T cells from p27 -/- Lck-Bcl-2 mice show delayed kinetics of CDK2 Thr-160 phosphorylation. This delay is associated with a delay in the up regulation of both Cyclin D2 and D3. These data demonstrate a complex relationship between the Bcl-2 family, cellular proliferation, and oncogenesis and demonstrate that p27 up-regulation is not singularly important in the proliferative delay observed in T cells expressing Bcl-2 family members. Nonetheless, the results indicate that p27 is a critical tumor suppressor in the context of Bcl-2 expression.
authors.affiliation: Department of Pathology, Program in Molecular and Cellular Biology, University of Iowa Roy J. and Lucille P. Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Ningli
authors.initials: N
authors.lastname: Cheng
authors.forename: Christopher I
authors.initials: CI
authors.lastname: van de Wetering
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D049109:Cell Proliferation; D056742:Cyclin D2; D056743:Cyclin D3; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C413374:p27 antigen; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2