8, 9 BIM is a tumor suppressor in mantle cell lymphoma, where the gene is lost, 10 as well as Burkitt’s lymphoma and renal carcinoma in which the gene is silenced. 5 BIM is also an important factor in peripheral T-cell apoptosis during the shutdown of an immune response. 6, 7 Constitutive loss of BIM (in all cell types) leads to the accumulation of lymphocytes that infiltrate non-hematopoietic organs, such as lungs, kidneys, liver and salivary glands, produce autoantibodies and on a mixed C57BL/6x129SV background this causes severe autoimmune disease resembling systemic lupus erythematosus. 5 During B- and T-cell development, BIM activity is required to eliminate autoreactive lymphocytes. 3īIM is a critical initiator of the mitochondrial apoptotic pathway, particularly in hematopoietic cells. 3, 4 Activated BAX and BAK oligomerize and form pores into the outer mitochondrial membrane, leading to the release of apoptogenic factors, such as cytochrome c, provoking the activation of the so-called caspase cascade with subsequent demolition of the cell. These BH3-only proteins activate the multi-domain members BAX and BAK either directly, or indirectly through neutralizing the pro-survival BCL-2 family members. Upon an apoptotic stimulus, the levels of certain BH3-only proteins increase as a result of transcriptional and/or post-transcriptional upregulation. 2 Pro-survival BCL-2 family members protect cells from dying through binding and neutralizing the pro-apoptotic BCL-2 family members. The latter can be further sub-divided into the BH3-only (BIM, PUMA, BID, BAD, NOXA, HRK, BMF, BIK) and the multi-BH domain members (BAX, BAK and possibly BOK). 1 This protein family can be divided into pro-survival (A1, MCL-1, BCL-2, BCL-XL and BCL-W) and pro-apoptotic members. The mitochondrial (also called intrinsic, stress or BCL-2 regulated) apoptotic pathway is regulated by members of the BCL-2 family. We have validated this novel conditional Bim knockout mouse model using established and newly developed CreER strains ( Rosa26-CreER and Vav-CreER) and will make these exciting new tools for studies on cell death and cancer available. This includes changes in thymocyte subpopulations, increased white blood cell counts and resistance of lymphocytes to BIM-dependent apoptotic stimuli, such as cytokine deprivation. We show that acute loss of BIM in the adult mouse rapidly results in the hematopoietic phenotypes previously observed in mice lacking BIM in all tissues. To address this issue and allow the deletion of BIM in specific cell types in future studies, we have developed a mouse strain with a conditional Bim allele as well as a new Cre transgenic strain, Vav-CreER, in which the tamoxifen-inducible CreER recombinase (fusion protein) is predominantly expressed in the hematopoietic system. It has been argued that the striking hematopoietic abnormalities of BIM-deficient mice (accumulation of lymphocytes and granulocytes) may be the result of the loss of the protein throughout the whole animal rather than a consequence intrinsic to the loss of BIM in hematopoietic cells. The pro-apoptotic BH3-only BCL-2 family member BIM is a critical determinant of hematopoietic cell development and homeostasis.
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