Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival.
Bcl-2 promotes oncogenesis by inhibiting cell death. Bcl-2 also inhibits proliferation and suppresses tumorigenesis in some settings. To clarify the role of the antiproliferative function of Bcl-2, mice expressing a mutant form of Bcl-2 reported to lack antiproliferative activity were generated (tyrosine 28 to alanine, Bcl-2-Y28A). As expected, both wild type (WT) and Bcl-2-Y28A inhibited apoptosis similarly. In contrast to previous results in cell lines, Bcl-2-Y28A inhibited T-cell proliferation identical to WT-Bcl-2. Significantly, both Bcl-2-Y28A and WT-Bcl-2 inhibited proliferation of T cells isolated from older animals, but not proliferation of T cells from immature mice. Instead, inhibition of cell activation correlated with T-cell size, p27 levels, and RNA content, all indicators of quiescent G0 arrest. Consistent with this model, Bcl-2 inhibition of T-cell proliferation was reversed by expression of Bax, again correlating cell proliferation with cell size. These experiments do not support genetically separate effects of Bcl-2 on apoptosis and proliferation. Instead, the data support a model in which Bcl-2 and Bax regulate T-cell proliferation by changes in T-cell size and by increasing the markers of quiescent G0 arrest. These changes likely result from prolonged T-cell survival.
Cheng
Ningli
N
Department of Pathology, The University of Iowa Roy J and Lucille P Carver College of Medicine, 3160 ML, Iowa City, IA 52242, USA.
Janumyan
Yelena M
YM
Didion
Lisa
L
Van Hofwegen
Chris
C
Yang
Elizabeth
E
Knudson
C Michael
CM
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002470:Cell Survival; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000032:analysis; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011754:Pyronine / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C058992:Tagln protein, mouse; D051028:bcl-2-Associated X Protein; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011754:Pyronine