title: Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2.
abstract: The Bcl-2 (Bcl is B-cell lymphocytic-leukaemia proto-oncogene) family comprises two groups of proteins with distinct functional biology in cell-fate signalling. Bcl-2 protein was the first member to be discovered and associated with drug resistance in human lymphomas. Since then a host of other proteins such as Bcl-xL, Bcl-2A1 and Mcl-1 with similar anti-apoptotic functions have been identified. In contrast, the pro-apoptotic Bcl-2 proteins contain prototypic effector proteins such as Bax and Bak, and the BH3 (Bcl-2 homology)-only proteins comprising Bak, Bid, Bim, Puma and Noxa. A complex interplay between the association of pro-apoptotic and anti-apoptotic proteins with each other determines the sensitivity of cancer cells to drug-induced apoptosis. The canonical functional of Bcl-2 in terms of apoptosis inhibition is its ability to prevent mitochondrial permeabilization via inhibiting the translocation and oligomerization of pro-apoptotic proteins such as Bax; however, more recent evidence points to a novel mechanism of the anti-apoptotic activity of Bcl-2. Overexpression of Bcl-2 increases mitochondrial oxygen consumption and in doing so generates a slight pro-oxidant intracellular milieu, which promotes genomic instability and blocks death signalling. However, in the wake of overt oxidative stress, Bcl-2 regulates cellular redox status thereby preventing excessive build-up of ROS (reactive oxygen species), which is detrimental to cells and tissues. Taken together, the canonical and non-canonical activities of Bcl-2 imply a critical involvement of this protein in the processes of tumour initiation and progression. In the present paper we review these functionally distinct outcomes of Bcl-2 expression with implications for the chemotherapeutic management of cancers.
authors.affiliation: Apoptosis, ROS and Cancer Biology Program, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Shefali
authors.initials: S
authors.lastname: Krishna
authors.forename: Ivan Cherh Chiet
authors.initials: IC
authors.lastname: Low
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
mesh_terms: D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2