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

PLoS One. 2008 Apr 2;3(4):e1911. doi: 10.1371/journal.pone.0001911.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD3 Complex / biosynthesis
  • Cell Proliferation
  • Cyclin D2
  • Cyclin D3
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Lymphoma, T-Cell / metabolism*
  • Mice
  • Mice, Transgenic
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • bcl-2-Associated X Protein / metabolism*


  • CD3 Complex
  • Ccnd2 protein, mouse
  • Ccnd3 protein, mouse
  • Cyclin D2
  • Cyclin D3
  • Cyclins
  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • p27 antigen
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2