Ranger Ann M, Zha Jiping, Harada Hisashi, Datta Sandeep Robert, Danial Nika N, Gilmore Andrew P, Kutok Jeffery L, Le Beau Michelle M, Greenberg Michael E, Korsmeyer Stanley J
Howard Hughes Medical Institute and Department of Pathology, Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9324-9. doi: 10.1073/pnas.1533446100. Epub 2003 Jul 22.
The proapoptotic activity of the "BH3-only" molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins proved viable, and most cell types appeared to develop normally. BAD did not exclusively account for cell death after withdrawal of survival factors, but it was an intermediate for epidermal growth factor- or insulin-like growth factor I-countered apoptosis, consistent with a "sensitizing" BH3-only molecule. Lymphocytes developed normally with no premalignant hyperplasia, but they displayed subtle abnormalities in proliferation and IgG production. Despite the minimal phenotype, Bad-deficient mice progressed, with aging, to diffuse large B cell lymphoma of germinal center origin. Exposure of Bad-null mice to sublethal gamma-irradiation resulted in an increased incidence of pre-T cell and pro-/pre-B cell lymphoblastic leukemia/lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage.
“仅含BH3结构域”分子BAD的促凋亡活性可通过生存因子信号传导进行差异调节。缺乏BAD长蛋白和BAD短蛋白的Bad基因缺陷小鼠被证明是可行的，并且大多数细胞类型似乎发育正常。BAD并非生存因子撤除后细胞死亡的唯一原因，但它是表皮生长因子或胰岛素样生长因子I对抗凋亡的一个中间介质，这与“致敏性”仅含BH3结构域分子一致。淋巴细胞正常发育，无癌前增生，但它们在增殖和IgG产生方面表现出细微异常。尽管表型轻微，但Bad基因缺陷小鼠随着年龄增长会发展为生发中心来源的弥漫性大B细胞淋巴瘤。将Bad基因敲除小鼠暴露于亚致死剂量的γ射线照射下，会导致前T细胞和前体/前B细胞淋巴细胞白血病/淋巴瘤的发病率增加。因此，促凋亡的BAD抑制淋巴细胞谱系中的肿瘤发生。
