BH3‐only Proteins

Abstract

The deregulation of programmed cell death, apoptosis, is a major contributor to the development of cancer and can impair the response of tumour cells to anticancer therapy. The Bcl‐2 family of proteins are critical regulators of apoptosis. BH3 (Bcl‐2 homologous 3)‐only proteins are pro‐apoptotic members that share with each other and the wider Bcl‐2 family only the BH3 domain that is critical for their killing capacity. These BH3‐only proteins promote cell death by directly or indirectly activating Bax and Bak , in a cell‐type and death stimulus‐specific manner. Studies of gene‐targeted mice that lack two or more BH3‐only proteins are beginning to unravel the overlapping functions of these apoptosis initiators. The activation or mimicking of these proteins is expected to improve the treatment of patients suffering from cancer or autoimmune diseases. Key concepts The ‘Bcl‐2‐regulated’ (also called ‘intrinsic’ or ‘mitochondrial’) apoptotic pathway is triggered by developmental cues or a broad range of cell stressors (e.g. growth factor deprivation, γ‐irradiation) and is regulated by the interplay of the pro‐ and antiapoptotic members of the Bcl‐2 family of proteins. The survival versus death fate of a cell is decided by the relative levels of pro‐ and antiapoptotic Bcl‐2 family members. During tumourigenesis defects in apoptosis signalling allow abnormal survival of cells undergoing neoplastic transformation and thereby facilitating sustained cell growth and accumulation of further oncogenic mutations. The Bcl‐2 family consists of three subgroups of proteins that can be differentiated on the basis of amino acid sequence, 3D structure and function. The pro‐survival members, Bcl‐2, Bcl‐x L , Bcl‐w (Bcl‐B), Mcl‐1 and A1, are essential for cell survival, with cell‐type specific expression. Two subfamilies encompass the apoptosis‐promoting Bcl‐2 family members: the multi‐BH domain pro‐apoptotic subfamily members Bax , Bak and Bok, and the BH3‐only subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa, Bmf and Puma/Bbc3. Bax, Bak (and Bok), are the critical activators of the effector phase of the intrinsic death pathway. Both Puma and Noxa, apoptosis initiators that are transcriptionally activated by p53 in response to DNA damage or oncogenic stress, can function as tumour suppressors in their own right, particularly in the context of an oncogenic lesion that subverts cell cycle control. It is important to bear in mind that apoptosis initiation constitutes only one of several critical mechanisms by which p53 suppresses tumour development. Bid functions as the link between the ‘death receptor’ and the ‘Bcl‐2‐regulated’ apoptotic pathways by causing an amplification of the caspase cascade that leads to cell destruction. Remarkably, Bid is critical for Fas ‘death receptor’‐induced apoptosis in certain cell types, such as hepatocytes, but dispensable in others, including lymphoid cells. Bim is critical for many physiologic and pathologic cell death processes and is a principal regulator of homeostasis in the lymphoid and myeloid compartment. Bim is crucial for the negative selection of autoreactive immature T‐ and B‐lymphoid cells, for growth factor deprivation‐induced apoptosis of many cell types and loss of BIM in certain human cancers substantiates its role as a tumour suppressor. BH3‐only proteins have a crucial function in chemotherapeutic drug‐induced killing of tumour cells and their loss is frequently associated with resistance to anticancer therapy. Mimicking BH3‐only proteins represents a promising strategy for enhancing the effects of conventional anticancer therapy and for treating autoimmune diseases whereas the blockade of these proteins may be beneficial in the management of certain degenerative diseases that are characterized by abnormal killing of cells that should be kept alive.

Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

“…In human tumors, mutations of PUMA or NOXA have rarely been documented, but loss of heterozygosity has been described for NOXA and multiple modes of abnormal reduction, including epigenetic silencing, overexpression of inhibitory microRNA, and deletion have been described for PUMA and BIM (reviewed in Happo et al 52 ). Our data indicate that inactivation of all 3 genes may result in drug resistance as severe as that seen for the loss of p53 or overexpression of Bcl-2 18 and thereby demonstrate the importance of understanding the status of these 3 BH3-only proteins for the prediction of drug response.…”

Puma, a critical mediator of cell death — one decade on from its discovery

“…2). The mutual cross-talk between p53 and PUMA is an excellent mechanism for preventing the growth and division of abnormal cells, thereby protecting them against the development of cancer [51]. p53-dependent activation of PUMA function occurs when cells receive a wide variety of stress signals.…”

Effect of collection methods on combustion particle physicochemical properties and their biological response in a human macrophage-like cell line

“…In several studies of urban particulate matter, PAHs content was negatively associated with particle-induced production of proinflammatory cytokines and chemokines in THP-1 cells, [57] in RAW 264.7 cells (a mouse ascites fluid macrophage-like cell line), [58] and in mouse lungs. [59,60] Jalava et al [58] suggested that PAHs induce immunosuppression and low cytokine production. For in vivo exposure of carbonaceous particles via instillation, Stoeger et al [61] found that the fraction of soluble organics was negatively associated proinflammatory response.…”