Mcl‐1; the molecular regulation of protein function

Thomas, Luke W.; Lam, Connie W.; Edwards, Steven W.

doi:10.1016/j.febslet.2010.05.061

Cited by 482 publications

(568 citation statements)

References 82 publications

(126 reference statements)

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“…MCL-1 has been reported to localize in different cellular compartments including cytosol, nuclear envelope, and mitochondria, depending on the cell type and the function that it has to perform (20). Although most of the studies reported mitochondrial localization, a very few reported cytosolic or nuclear localization of this protein (46,47).…”

Section: Discussionmentioning

confidence: 99%

“…Under normal physiological conditions, MCL-1 expression is rigidly controlled at different levels, involving transcriptional, post-transcriptional, and posttranslational regulations (20). Experiments with conditional knock-out mice documented the indispensability of MCL-1 in the survival of many cell types including lymphocytes (21), hematopoietic stem cells (22), and neutrophils (23), whereas other anti-apoptotic BCL-2 family members were found to be more dispensable (21)(22)(23).…”

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confidence: 99%

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Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

Giri

Srivastav

Basu

et al. 2016

Journal of Biological Chemistry

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Apoptosis is one of the mechanisms used by host cells to remove unwanted intracellular organisms, and often found to be subverted by pathogens through use of host anti-apoptotic proteins. In the present study, with the help of in vitro and in vivo approaches, we documented that the macrophage anti-apoptotic protein myeloid cell leukemia 1 (MCL-1) is exploited by the intra-macrophage parasite Leishmania donovani to protect their "home" from actinomycin D-induced mitochondria-dependent apoptosis. Among all the anti-apoptotic BCL-2 family members, infection preferentially up-regulated expression of MCL-1 at both the mRNA and protein levels and compared with infected control, MCL-1-silenced infected macrophages documented enhanced caspase activity and increased apoptosis when subjected to actinomycin D treatment. Phosphorylation kinetics and ChIP assay demonstrated that infection-induced MCL-1 expression was regulated by transcription factor CREB (cAMP-response element-binding protein) and silencing of CREB resulted in reduced expression of MCL-1 and increased apoptosis. During infection, MCL-1 was found to be localized in mitochondria and this was significantly reduced in Tom70-silenced macrophages, suggesting the active role of TOM70 in MCL-1 transport. In the mitochondria, MCL-1 interacts with the major pro-apoptotic protein BAK and prevents BAK-BAK homo-oligomer formation thereby preventing cytochrome c release-mediated mitochondrial dysfunction. Silencing of MCL-1 in the spleen of infected mice showed decreased parasite burden and increased induction of splenocyte apoptosis. Collectively our results showed that L. donovani exploited the macrophage anti-apoptotic protein MCL-1 to prevent BAK-mediated mitochondria-dependent apoptosis thereby protecting its niche, which is essential for disease progression.Leishmania donovani, an obligate intracellular parasite, is the causative agent of the fatal visceral leishmaniasis (1). After entry into the macrophages, it survives and replicates inside the acidified phagolysosomes of macrophages (2). Its persistence to resist the host immune system determines the extent of pathogenicity and requires extensive manipulation of macrophage defense (3). One of the vital mechanisms by which host cells defend themselves against intracellular pathogens is the induction of apoptosis (4, 5). On the contrary, pathogens relentlessly try to defeat the host defense systems and evolved a number of ways to inhibit host cell apoptosis, which allows them more time to replicate (6). Various studies have documented the molecular mechanisms in virus (7), bacteria (8), and protozoan parasites (9) that tamper with the host defensive apoptotic machinery. Leishmania, being an obligate intracellular parasite, makes host cells resistant to a variety of pro-apoptotic signals in murine and human cell lines. L. donovani infection protects bone marrow-derived macrophages (BMDM) 2 from growth factor withdrawal-induced apoptosis (10). Infection with Leishmania infantum reduces actinomycin D-induced cell dea...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

Giri

Srivastav

Basu

et al. 2016

Journal of Biological Chemistry

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“…We designed alanine substitutions to remove PEST phosphorylation sites from Mcl-1, including those that stabilize (e.g. Thr-92 and Ser-121), or destabilize (Ser-159, and Thr-163) the protein upon phosphorylation (17). These constructs were transiently transfected into HCT116 p53 Ϫ/Ϫ cells with stable knockdown of Mcl-1.…”

Section: Posttranslational Modification Sites and Bh Domains Are Dispmentioning

confidence: 99%

Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain

Demelash

Pfannenstiel

Tannenbaum

et al. 2015

Journal of Biological Chemistry

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Background:Mcl-1 is a prosurvival gene critical for chemotherapy resistance. However, its antisenescence properties are poorly characterized. Results: Through mutagenesis of Mcl-1 in functional assays, we identified a loop domain required for inhibiting senescence. Conclusion: An internal loop domain of Mcl-1 is responsible for antisenescence functions. Significance: Our study provides additional targets within Mcl-1 that can enhance senescence-inducing cancer treatments.

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“…Cytochrome c induces the activation of caspases lead to the macromolecular degradation of apoptotic process. 29 PKC-B inhibitor is shown to be effective in combination with PLK-1 inhibitors in the absence of p53. 37 Based on the previous findings that anti-tubulin chemotherapeutics, 23 and vinca alkaloids in combination with PLK-1 inhibition, 38 induce prolonged mitotic arrest followed by apoptosis through down regulation of Mcl-1, we have tested the role of Mcl-1 in apoptosis induced by inhibition PLK-1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Nair

Schwartz

2015

Cell Cycle

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Sarcomas are rare cancers and the current treatments in inoperable or metastatic disease have not been shown to prolong survival. In order to develop novel targeted therapies, we tested the efficacy of polo-like kinase 1 (PLK-1) inhibitor (TAK-960) in sarcoma. All the sarcoma cell lines were sensitive to TAK-960 with IC50s in the low nanomolar range. We chose MPNST, CHP100 and LS141 for our studies and of which MPNST cells exclusively underwent polyploidy after a delay in mitosis for about 18 hours; CHP100 cells, after a 24h mitotic delay, died of apoptosis; LS141, after a delay in mitosis stayed at 4N with mild apoptosis. Apoptosis induced by TAK-960 in CHP100 was associated with downregulation of Mcl-1 and the effect was recapitulated by down-regulating PLK1 by siRNA, confirming that the effect of TAK-960 on Mcl-1 expression is target specific. With suppression of Mcl-1 by siRNA, TAK-960 induced apoptosis in MPNST cells as well. These effects were confirmed in vivo, such that TAK-960 more effectively inhibited CHP100 than MPNST xenografts. In the setting of PLK-1 inhibition, Mcl-1 down regulation is shown to be an important determinant of apoptosis. Collectively, the net effect of this is to drive cells to apoptosis, resulting in a greater anti-tumor effect in vivo. Therefore, targeting PLK-1 should have a greater impact in treating sarcomas provided there is concomitant suppression of Mcl-1. These results further indicate that Mcl-1 could be an important biomarker to predict sensitivity to the induction of apoptosis by PLK-1 targeted therapy in sarcoma.

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Mcl‐1; the molecular regulation of protein function

Cited by 482 publications

References 82 publications

Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

Leishmania donovani Exploits Myeloid Cell Leukemia 1 (MCL-1) Protein to Prevent Mitochondria-dependent Host Cell Apoptosis

Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

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