p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma

Ningli Cheng; Christopher I van de Wetering; C Michael Knudson

doi:10.1371/journal.pone.0001911

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p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma

Journal article

Open access

Peer reviewed

p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma

Ningli Cheng, Christopher I van de Wetering and C Michael Knudson

PloS one, Vol.3(4), pp.e1911-e1911

04/02/2008

DOI: 10.1371/journal.pone.0001911

PMCID: PMC2270898

PMID: 18382684

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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.

Cyclin-Dependent Kinase 2 - metabolism

Cell Proliferation

Gene Expression Regulation, Neoplastic

Thymus Gland - cytology

bcl-2-Associated X Protein - metabolism

Mice, Transgenic

CD3 Complex - biosynthesis

Cyclin D3

Cyclin D2

Lymphoma, T-Cell - metabolism

Proliferating Cell Nuclear Antigen - physiology

Proto-Oncogene Proteins c-bcl-2 - metabolism

Animals

Proliferating Cell Nuclear Antigen - genetics

Cyclins - metabolism

T-Lymphocytes - metabolism

Mice

Details

Title: Subtitle: p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma
Creators: Ningli Cheng - 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
Christopher I van de Wetering
C Michael Knudson
Resource Type: Journal article
Publication Details: PloS one, Vol.3(4), pp.e1911-e1911
DOI: 10.1371/journal.pone.0001911
PMID: 18382684
PMCID: PMC2270898
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: F31 CA103363 / NCI NIH HHS F31CA103363 / NCI NIH HHS 1R01CA88967 / NCI NIH HHS R01 CA104695 / NCI NIH HHS R01 CA088967 / NCI NIH HHS 1R01CA104695 / NCI NIH HHS
Language: English
Date published: 04/02/2008
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984047644602771

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