Emerging role of Mcl-1 in actively counteracting BH3-only proteins in apoptosis

Zhuang, Jianguo; Brady, Hugh J.M.

doi:10.1038/sj.cdd.4401952

Cited by 21 publications

(14 citation statements)

References 67 publications

(79 reference statements)

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“…Because the MEK/ERK pathway has been demonstrated to decrease levels of Bim and Mcl1 has been shown to be a critical regulator of Bim function, we also examined Egr2-mediated regulation of Bim. We observed a decrease in Bim protein modulated by Egr2 function with no concomitant effect on Bim expression (63,64). We did not observe changes in expression of pro-apoptotic Bcl2 family members Bax and Bak.…”

Section: Discussionmentioning

confidence: 53%

Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway

Bradley

Ruan

Oursler

2008

Journal of Biological Chemistry

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Although bone in young adults is continually resorbed and rebuilt in a balanced manner, unbalanced bone loss results from increased bone resorption without concomitant replacement with an equal amount of new bone. Osteoclastic bone resorption is governed primarily by the numbers of osteoclasts present at the site of bone remodeling and the activity of those osteoclasts (1). Therefore, factors affecting osteoclastogenesis and osteoclast survival are key to regulating the amount of bone resorbed. Macrophage colony-stimulating factor (M-CSF) 2 and receptor activator for nuclear factor-B ligand (RANKL) are two cytokines both necessary and sufficient to mediate osteoclast differentiation from hematopoietic cells within the monocyte/macrophage lineage (2, 3). M-CSF binds to the receptor tyrosine kinase member c-fms, which then activates intracellular signaling through an autophosphorylation event (4). Although M-CSF is known to promote osteoclast survival, the mechanism by which M-CSF mediates survival is unknown. Mitogen-activated protein (MAP) kinases are specific protein kinases influencing cell proliferation, differentiation, and survival. All three MAP kinase pathways, namely the MEK/ERK, p38 MAPK, and c-Jun NH 2 -terminal kinase pathways, play roles in osteoclasts either in differentiation and/or in mediating osteoclast function and survival (5-9). Thus, activation of these pathways is crucial in modulating bone resorption rates. Chemical inhibition of MEK1/2, which inhibits the phosphorylation of the MAP kinases ERK1/2, increases osteoclast apoptosis and leads to a loss of cell polarity (5, 7). Once activated by MEK, ERK modulates cell cycle regulation and post-mitotic functions (10). In osteoclasts, ERK activation has been demonstrated to influence survival (5, 7, 9). Although the MEK/ERK pathway influences osteoclast survival, the mechanism of activation and downstream effectors of this pathway remain unresolved.M-CSF promotes expression of the early gene response (Egr) family of transcription factors during macrophage differentiation (11). This immediate early gene family is part of the Kruppel-like zinc finger transcription factor family and is comprised of Egr1, Egr2, Egr3, Egr4, and the Wilms' Tumor transcription factor. Egr1, Egr2, and Egr3 contain a repressor domain involved in binding of two corepressors, Nab1 and Nab2 (12, 13). Although the zinc finger binding domains of the Egr family members are virtually identical, the remaining domains differ significantly, implying unique functions for each of these transcription factors (14). Egr1 up-regulation in prostate cancer cells is thought to promote cell growth and transformation through increased expression of cyclin D1 (15, 16). However, Egr1 expression is either down-regulated or promotes apoptosis in other cancer cell lines (17-19), indicating cell-type specific responses. Egr2 expression has been primarily reported to promote apoptosis through transactivation of p53, FasL, Bak, and BNIP3 or suppress proliferation through PTEN expression (20 -22). To...

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Section: Discussionmentioning

confidence: 53%

Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway

Bradley

Ruan

Oursler

2008

Journal of Biological Chemistry

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“…This protein was present at high levels in most primary CLL B-cell samples, but was either not expressed or was predominantly detected as a phosphorylated and presumably inactive protein in the 2 resistant cell lines. Since one of the best known functions of Mcl-1 is to sequester Bim and thereby prevent Bax and Bak activation, [48][49][50] it would seem reasonable to postulate that high levels of Bim may be responsible for the marked dependence of CLL cells on Mcl-1 expression. However, in a very recent study, Del Gaizo Moore et al 51 observed that most of Bim in CLL B cells is already complexed with Bcl-2, indicating that Mcl-1 may also increase the apoptosis resistance of CLL B cells through mechanisms that do not involve direct interactions with Bim.…”

Section: Discussionmentioning

confidence: 99%

The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells

Longo

Laurenti

Gobessi

et al. 2008

Blood

279

256

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“…Mcl-1 is known to block apoptosis at the mitochondria level by interacting and inhibiting the action of Bcl-2 proapoptotic proteins (55). Melanoma cells are type II cells, and in these cells, the weak activation of caspase-8 at the death-inducing signaling complex activates the mitochondria death pathway and subsequently caspase-3, which in turn leads to the processing of the large majority of caspase-8 and to the amplification of the weak initiating signal generated at the death-inducing signaling complex.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

Chetoui

Sylla

Gagnon-Houde

et al. 2008

Molecular Cancer Research

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Resistance of malignant melanoma cells to Fas-mediated apoptosis is among the mechanisms by which they escape immune surveillance. However, the mechanisms contributing to their resistance are not completely understood, and it is still unclear whether antiapoptotic Bcl-2 -related family proteins play a role in this resistance. In this study, we report that treatment of Fas-resistant melanoma cell lines with cycloheximide, a general inhibitor of de novo protein synthesis, sensitizes them to anti-Fas monoclonal antibody (mAb) -induced apoptosis. The cycloheximide-induced sensitization to Fas-induced apoptosis is associated with a rapid down-regulation of Mcl-1 protein levels, but not that of Bcl-2 or Bcl-xL. Targeting Mcl-1 in these melanoma cell lines with specific small interfering RNA was sufficient to sensitize them to both anti-Fas mAb-induced apoptosis and activation of caspase-9.

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Emerging role of Mcl-1 in actively counteracting BH3-only proteins in apoptosis

Cited by 21 publications

References 67 publications

Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway

Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway

The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

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