Mitochondrial factors with dual roles in death and survival

Wc, Cheng; Berman, Sarah B.; Ivanovska, Iva; Ea, Jonas; Sj, Lee; Y, Chen; Kaczmarek, L. K.; Pineda, Fernando; Hardwick, J. Marie

doi:10.1038/sj.onc.1209596

Cited by 67 publications

(44 citation statements)

References 131 publications

(149 reference statements)

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“…40 Besides sensing and transducing various survival or death signals to mitochondria to regulate apoptosis, more and more 'non-canonical' functions of Bcl-2 family members have been identified. 41 We have demonstrated that Bid, a BH3-only Bcl-2 family member regulates the response of LSK cells and early progenitor cells to replicative stress. Investigating the physiological function of these novel properties of Bcl-2 members will deepen our understanding of Bcl-2 family in the hematopoietic system.…”

Section: Discussionmentioning

confidence: 99%

Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress

2012

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Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin À Sca1 þ Kit þ (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid À / À MPCs demonstrate increased sensitivity to HU and are depleted. Bid À / À LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid À / À MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid À / À mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.

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Section: Discussionmentioning

confidence: 99%

Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress

2012

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“…In healthy cells, BAX and BAK influence the dynamics of mitochondrial tubules by controlling mitochondrial fusion and fission, processes known to dynamically control the mitochondrial network affecting the efficiency of fuel oxidation, ATP synthesis and Ca 2 þ buffering (Karbowski et al, 2006). The above findings are but four examples of an emerging notion that BCL-2 family members are integral components of distinct cellular homeostatic pathways that carry 'day jobs' separate from their capacity to regulate apoptosis (Danial and Korsmeyer, 2004;Cheng et al, 2006). By being embedded in these processes, they serve as critical checkpoints for death when cellular homeostasis is violated.…”

Section: Introductionmentioning

confidence: 99%

BAD: undertaker by night, candyman by day

2008

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The BH3-only pro-apoptotic proteins are upstream sensors of cellular damage that selectively respond to specific, proximal death and survival signals. Genetic models and biochemical studies indicate that these molecules are latent killers until activated through transcriptional or post-translational mechanisms in a tissue-restricted and signal-specific manner. The large number of BH3-only proteins, their unique subcellular localization, protein-interaction network and diverse modes of activation suggest specialization of their damage-sensing function, ensuring that the core apoptotic machinery is poised to receive input from a wide range of cellular stress signals. The apoptotic response initiated by the activation of BH3-only proteins ultimately culminates in allosteric activation of pro-apoptotic BAX and BAK, the gateway proteins to the mitochondrial pathway of apoptosis. From activation of BH3-only proteins to oligomerization of BAX and BAK and mitochondrial outer membrane permeabilization, an intricate network of interactions between the pro-and anti-apoptotic members of the BCL-2 family orchestrates the decision to undergo apoptosis. Beyond regulation of apoptosis, multiple BCL-2 proteins have recently emerged as active components of select homeostatic pathways carrying other cellular functions. This review focuses on BAD, which was the first BH3-only protein linked to proximal survival signals through phosphorylation by survival kinases. In addition to findings that delineated the physiological role of BAD in apoptosis and its dynamic regulation by phosphorylation, studies pointing to new roles for this protein in other physiological pathways, such as glucose metabolism, are highlighted. By executing its 'day' and 'night' jobs in metabolism and apoptosis, respectively, BAD helps coordinate mitochondrial fuel metabolism and the apoptotic machinery.

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“…This interaction may be favored by the cancer-specific overexpression of mitochondrion-binding hexokinase isoenzymes (Mathupala et al, 2006) or by activation of the Akt pathway, which stimulates the interaction between hexokinase and VDAC (Robey and Hay, 2006). Another hint to a possible one-step scenario comes from the observation that members of the Bcl-2 family have apoptosis-unrelated functions (or 'day jobs') that may connect metabolic control and apoptosis regulation, although the details of this crosstalk remain largely unexplored (Cheng et al, 2006). These facts and hypotheses do not constitute a merely academic playground.…”

Section: Mitochondria In Cancermentioning

confidence: 99%

“…MOMP is an extremely complex phenomenon that is regulated by proteins from the Bcl-2 family (Cheng et al, 2006), proteins contained in the permeability transition pore complex (Brenner and Grimm, 2006), proteins that affect mitochondrial dynamics (fusion and fission) (Alirol and Martinou, 2006;Cereghetti and Scorrano, 2006) and even transcription factors (such as the tumor-suppressor protein p53) that can translocate from the nucleus to mitochondria to stimulate MOMP (Moll et al, 2006). MOMP inhibition resulting in disabled apoptosis is important for the development of solid tumors.…”

Section: Mitochondria In Cancermentioning

confidence: 99%