Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells.
The bcl-2 gene was first discovered by molecular analysis of the 14;18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes because, rather than promoting cell proliferation, it fosters cell survival. This review summarizes the impact of constitutive bcl-2 expression on the development and function of lymphocytes as well as their malignant transformation. Expression of a bcl-2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the genetic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from bcl-2 transgenic mice were remarkably resistant to diverse cytotoxic agents. Nevertheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the development of B lymphoid tumours but at relatively low frequency and with long latency. Co-expression of myc and bcl-2, on the other hand, promoted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of the bcl-2 transgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to supplement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of the bcl-2 transgenic mice with p53-/- mice have addressed whether loss of p53 function and gain of bcl-2 function are synergistic for lymphoid cell survival.
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
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Cory
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Harris
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Strasser
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001402:B-Lymphocytes / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D006706:Homeostasis; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D013601:T-Lymphocytes / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2