Bad -deficient mice develop diffuse large B cell lymphoma

Abstract

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 ␥-irradiation resulted in an increased incidence of pre-T cell and pro-͞pre-B cell lymphoblastic leukemia͞ lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage.

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

“…Second, anti-BNIP3 therapy might not necessarily need to be given specifically to the myocardium. The germ-line BNIP3 knockout mouse showed no detectable developmental or functional abnormalities in any organ system, including the hematopoietic system wherein increased numbers of lymphoid, myeloid and erythroid cells have been described for other BH3-only factor gene knockout models (Bouillet et al, 1999;Ranger et al, 2003;Diwan et al, 2007a). This is consistent with the concept that BNIP3 functions almost exclusively in an inducible manner, and that ischemia is critical to increase its expression and possibly to activate it post-translationally (Kubasiak et al, 2002;Kubli et al, 2008).…”

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…53 Mice lacking BAD are largely normal, and their cells do not show marked resistance to the apoptotic stimuli tested. 54,55 The role of BAD in programmed and stress-induced cell death is therefore probably relatively subtle and ancillary to the action of more potent BH3-only proteins (e.g., BIM, PUMA). Phosphorylation of BIM by ERK was reported to be critical for the antiapoptotic activity of this kinase.…”

“…In this experimental model, NOXA and BMF have been shown to suppress lymphoma development, 110,111 while the role of BAD remains contentious with one report describing accelerated thymic lymphomagenesis in BAD-deficient mice while another publication reported no effect. 54,55 Possible explanations for the discrepancy might include differences in γ-radiation dosing and schedule used or differences in genetic background (C57BL/6 55 versus complicated mixed background 54 ). Loss of BIM alone did not accelerate lymphoma development; however, mice deficient for both BAD and BIM showed accelerated tumour development.…”

BCL2 family in DNA damage and cell cycle control

“…18,47 This effect is completely dependent on BAD binding to BCL-x L and BCL2; therefore, it is not surprising that deficiency of BAD itself is only minimally oncogenic. 48 …”

“…Absence of proapoptotic BH3-only molecules results in spontaneous malignancy in mouse models lacking BID and BAD. 48,54 However, the absence of multi-domain BAX or BAK results in prominent inhibition of apoptosis emanating from both intrinsic and extrinsic pathways with resultant abrogation of homeostatic control. 79 Despite this potent perturbation of apoptosis, to date, bax À/À or bak mice do not progress to malignancy.…”