p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma.
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.
Cheng
Ningli
N
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.
van de Wetering
Christopher I
CI
Knudson
C Michael
CM
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*
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