Individual and overlapping roles of BH3-only proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development

Abstract

BH3-only proteins, such as Bim and Bad, contribute to tissue homeostasis by initiating apoptosis in a cell type- and stimulus-specific manner. Loss of Bim provokes lymphocyte accumulation in vivo and renders lymphocytes more resistant to diverse apoptotic stimuli and Bad has been implicated in the apoptosis of hematopoietic cells upon cytokine deprivation. To investigate whether their biological roles in apoptosis overlap, we generated mice lacking both Bim and Bad and compared their hematopoietic phenotype with that of the single-knockout and wild-type (wt) animals. Unexpectedly, bad−/− mice had excess platelets due to prolonged platelet life-span. The bim−/−bad−/− mice were anatomically normal and fertile. Their hematopoietic phenotype resembled that of bim−/− mice but lymphocytes were slightly more elevated in their lymph nodes. Although resting B and T lymphocytes from bim−/−bad−/− and bim−/− animals displayed similar resistance to diverse apoptotic stimuli, mitogen-activated bim−/−bad−/− B cells were more refractory to cytokine deprivation. Moreover, combined loss of Bim and Bad enhanced survival of thymocytes after DNA damage and accelerated development of γ-irradiation-induced thymic lymphoma. Unexpectedly, their cooperation in the thymus depended upon thymocyte-stromal interaction. Collectively, these results demonstrate that Bim and Bad can cooperate in the apoptosis of thymocytes and activated B lymphocytes and in the suppression of thymic lymphoma development.

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

“…Loss of BIM alone did not accelerate lymphoma development; however, mice deficient for both BAD and BIM showed accelerated tumour development. 55 Remarkably, loss of PUMA completely abrogated γ-radiation-induced thymic lymphoma development. 111,112 This striking finding could be attributed to the profound resistance of PUMA-deficient white blood cells to DNA damage-induced apoptosis.…”

“…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.…”

BH3-only proteins in apoptosis at a glance

“…Bad -/-mice appear normal (Ranger et al, 2003), except for a mild thrombocytosis (Kelly et al, 2010) that is probably caused by reduced inhibition of BCL-X L in the absence of BAD (Mason et al, 2007). Mouse embryonic fibroblasts (MEFs) lacking BAD remain sensitive to many apoptotic stimuli (Ranger et al, 2003).…”

The Role of the Apoptotic Machinery in Tumor Suppression

“…However, given that loss of BAD (Ranger et al 2003) or even combined loss of BAD and BIM (Kelly et al 2010) had only minimal effects on cell survival indicates that this process is not critical for sustaining survival of cells undergoing transformation. AKT has also been shown to promote cell survival by phosphorylating FOXO3a, thereby preventing this transcription factor from activating its target genes, such as the proapoptotic BH3-only gene Bim (O'Connor et al 1998;Dijkers et al 2000).…”