{"title":"Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer.","authors":"Mariusz L Hartman","doi":"10.1038/s41419-024-07307-z","DOIUrl":null,"url":null,"abstract":"<p><p>Apoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"917"},"PeriodicalIF":8.1000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-024-07307-z","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Apoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism