Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction

Abstract

The physiological role of B cell lymphoma 2 (Bcl-2) homology 3–only proteins has been investigated in mice lacking the individual genes identifying rate-limiting roles for Bim (Bcl-2–interacting mediator of cell death) and Puma (p53–up-regulated modulator of apoptosis) in apoptosis induction. The loss of Bim protects lymphocytes from apoptosis induced by cytokine deprivation and deregulated Ca++ flux and interferes with the deletion of autoreactive lymphocytes and the shutdown of immune responses. In contrast, Puma is considered the key mediator of p53-induced apoptosis. To investigate the hypothesis that Bim and Puma have overlapping functions, we generated mice lacking both genes and found that bim−/−/puma−/− animals develop multiple postnatal defects that are not observed in the single knockout mice. Most strikingly, hyperplasia of lymphatic organs is comparable with that observed in mice overexpressing Bcl-2 in all hemopoietic cells exceeding the hyperplasia observed in bim−/− mice. Bim and Puma also have clearly overlapping functions in p53-dependent and -independent apoptosis. Their combined loss promotes spontaneous tumorigenesis, causing the malignancies observed in Bcl-2 transgenic mice, but does not exacerbate the autoimmunity observed in the absence of Bim.

Apoptosis in the development of the immune system

“…Mice lacking both BIM and PUMA exhibit an even more dramatic increase in the number of peripheral lymphocytes than mice solely lacking BIM. 48 Thymocytes from these mice are also much more resistant to a variety of cell death stimuli than mice lacking either BIM or PUMA alone. 48 The multidomain proapoptotic members, BAX and BAK, have been demonstrated to be the critical mediators of apoptotic signaling downstream of the action of BH3-only family members.…”

“…48 Thymocytes from these mice are also much more resistant to a variety of cell death stimuli than mice lacking either BIM or PUMA alone. 48 The multidomain proapoptotic members, BAX and BAK, have been demonstrated to be the critical mediators of apoptotic signaling downstream of the action of BH3-only family members. Embryos and mice doubly-deficient for both BAX and BAK possess multiple abnormalities in cellular homeostasis, including in the immune system.…”

“…47 Thymocytes from mice lacking both BIM and PUMA demonstrate an increased resistance to death by neglect, indicating that both BIM and PUMA act to mediate death owing to growth factor withdrawal during T-cell development. 48 However, in developing B-cells loss of BIM and PUMA is no different than loss of BIM alone, suggesting another BH3-only may act with BIM to regulate early B-cell development. These data suggest that PUMA and BIM may act in concert to regulate cell death downstream of growth factor withdrawal in some cell types.…”

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

“…[141][142][143][144][145] PUMA and BIM together account for most of the proapoptotic activity of glucocorticoids. 141,143,[146][147][148][149] BIM is also critical for taxane-induced cell killing. 150,151 Furthermore, BMF as well as BIM are critical for the killing of non-transformed lymphoid cells as well as certain lymphoma cells by inhibitors of histone deacetylases.…”

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

“…In contrast, Jnk1 knockdown attenuates Bim and PUMA upregulation by loss of Keap1, a result consistent with previous studies. 5,47 Bim and PUMA cooperate in cell death processes 48 by directly activating the mitochondrial pathway of apoptosis. 5,15 Saturated FFAinduced mitochondrial dysfunction results in the egress of mitochondrial pro-apoptotic mediators into the cytosol.…”