BH3‐only Proteins
Authors: Happo Lina , Strasser Andreas , Scott Clare L 
Published: September 2009

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 activatingBaxandBak, 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‐xL, 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 membersBax,Bakand 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.