Saga of Mcl-1: regulation from transcription to degradation

Senichkin, Viacheslav V; Streletskaia, Alena Y; Горбунова, А. С.; Zhivotovsky, Boris; Kopeina, Gelina S.

doi:10.1038/s41418-019-0486-3

Cited by 104 publications

(93 citation statements)

References 149 publications

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“…This is due to the presence of a N-terminal sequence rich in proline (P), glutamic acid (E), serine (S) and threonine (T) residues (PEST). The PEST sequence regulates MCL-1 turnover and the post-translational modifications (recently reviewed by Senichkin et al [ 13 ]).…”

Section: Multi-functional Roles Of Mcl-1mentioning

confidence: 99%

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

et al. 2020

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Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.

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Section: Multi-functional Roles Of Mcl-1mentioning

confidence: 99%

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

et al. 2020

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“…In particular, we find that MCL1 plays an important role in the regulation of FK in response to MAPK pathway inhibition. MCL1 expression may be inherently highly variable between cells due to the short half-life of MCL1 mRNA and the instability of the protein ( Senichkin et al, 2020 ). Our pharmacological, imaging, and overexpression studies suggest that differences in the rate of FK are linked in part to variation in MCL1 protein expression between cells within the population, with the ability to accumulate higher levels of MCL1 in a given cell associated with later onset of cell death ( Figure 6G ).…”

Section: Discussionmentioning

confidence: 99%

Kinetic Heterogeneity of Cancer Cell Fractional Killing

et al. 2020

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SUMMARY Lethal drugs can induce incomplete cell death in a population of cancer cells, a phenomenon referred to as fractional killing. Here, we show that high-throughput population-level time-lapse imaging can be used to quantify fractional killing in response to hundreds of different drug treatments in parallel. We find that stable intermediate levels of fractional killing are uncommon, with many drug treatments resulting in complete or near-complete eradication of all cells, if given enough time. The kinetics of fractional killing over time vary substantially as a function of drug, drug dose, and genetic background. At the molecular level, the antiapoptotic protein MCL1 is an important determinant of the kinetics of fractional killing in response to MAPK pathway inhibitors but not other lethal stimuli. These studies suggest that fractional killing is governed by diverse lethal stimulus-specific mechanisms.

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“…Bcl-2 proteins share up to four evolutionarily conserved Bcl-2 homology (BH) domains, which are important for their function. While anti-apoptotic Bcl-2, Bcl-X L and Bcl-w contain four eBH domains (BH1-4), Mcl-1 lacks the BH4 domain [5]. Mcl-1 also has a distinct Nterminal domain with regions enriched in proline, glutamic acid, serine, and threonine (PEST) residues, which ensures its rapid proteasomal degradation [5].…”

Section: Introductionmentioning

confidence: 99%

“…While anti-apoptotic Bcl-2, Bcl-X L and Bcl-w contain four eBH domains (BH1-4), Mcl-1 lacks the BH4 domain [5]. Mcl-1 also has a distinct Nterminal domain with regions enriched in proline, glutamic acid, serine, and threonine (PEST) residues, which ensures its rapid proteasomal degradation [5]. Thus, Mcl-1 has a much shorter half-life compared to other Bcl-2 family proteins [6].…”

Section: Introductionmentioning

confidence: 99%

Mcl-1-mediated mitochondrial fission protects against stress but impairs cardiac adaptation to exercise

Moyzis

Lally

Liang

et al. 2020

Journal of Molecular and Cellular Cardiology

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Myeloid cell leukemia-1 (Mcl-1) is a structurally and functionally unique anti-apoptotic Bcl-2 protein. While elevated levels of Mcl-1 contribute to tumor cell survival and drug resistance, loss of Mcl-1 in cardiac myocytes leads to rapid mitochondrial dysfunction and heart failure development. Although Mcl-1 is an anti-apoptotic protein, previous studies indicate that its functions extend beyond regulating apoptosis. Mcl-1 is localized to both the mitochondrial outer membrane and matrix. Here, we have identified that Mcl-1 in the outer mitochondrial membrane mediates mitochondrial fission, which is independent of its anti-apoptotic function. We demonstrate that Mcl-1 interacts with Drp1 to promote mitochondrial fission in response to various challenges known to perturb mitochondria morphology. Induction of fission by Mcl-1 reduces nutrient deprivation-induced cell death and the protection is independent of its BH3 domain. Finally, cardiac-specific overexpression of Mcl-1 OM , but not Mcl-1 Matrix , contributes to a shift in the balance towards fission and leads to reduced exercise capacity, suggesting that a pre-existing fragmented mitochondrial network leads to decreased ability to adapt to an acute increase in workload and energy demand. Overall, these findings highlight the importance of Mcl-1 in maintaining mitochondrial health in cells.

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Saga of Mcl-1: regulation from transcription to degradation

Cited by 104 publications

References 149 publications

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Kinetic Heterogeneity of Cancer Cell Fractional Killing

Mcl-1-mediated mitochondrial fission protects against stress but impairs cardiac adaptation to exercise

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