Other entities represented in this entry:
HGNC Approved Gene Symbol: MCL1
Cytogenetic location: 1q21.2 Genomic coordinates (GRCh38): 1:150,574,558-150,579,610 (from NCBI)
MCL1 is a potent multidomain antiapoptotic protein of the BCL2 (151430) family that heterodimerizes with other BCL2 family members to protect against apoptotic cell death (Mott et al., 2007).
Kozopas et al. (1993) isolated a gene, MCL1, from the ML-1 human myeloid leukemia cell line. Expression of MCL1 increased early in the induction, or programming, of differentiation in ML-1 (at 1-3 hr), before the appearance of differentiation markers and mature morphology (at 1-3 days). MCL1 showed sequence similarity, particularly in the carboxyl portion, to BCL2 (151430), a gene involved in normal lymphoid development and in lymphomas with the t(14;18) chromosome translocation. Further, in contrast to proliferation-associated oncogenes, the expression of MCL1 and BCL2 relates to the programming of differentiation/development and cell viability/death. Kozopas et al. (1993) suggested that MCL1 and BCL2 are 2 members of a 'new' gene family.
Bae et al. (2000) identified a short splicing variant of MCL1, which they termed MCL1S. Sequence analysis indicated that the 271-amino acid variant lacks BCL2 homology domains 1 and 2 and the transmembrane domain due to the splicing out of exon 2 during mRNA processing. Unlike the full-length 350-amino acid MCL1 protein (MCL1L), yeast 2-hybrid analysis showed that MCL1S does not interact with proapoptotic BCL2 family proteins but dimerizes with the antiapoptotic MCL1L. Overexpression of MCL1S induced apoptosis in transfected CHO cells that could be antagonized by a caspase inhibitor or specifically by MCL1L. Therefore, the authors concluded that the fate of MCL1-expressing cells may be regulated through alternative splicing mechanisms and the interactions of the resulting gene products.
The p53 protein (191170) is an important proapoptotic regulator. Leu et al. (2004) found that after cell stress, p53 interacted with BAK (600516). This interaction caused oligomerization of BAK and release of cytochrome c from mitochondria. Formation of the p53-BAK complex coincided with loss of an interaction between BAK and the antiapoptotic protein MCL1. Leu et al. (2004) suggested that p53 and MCL1 have opposing effects on mitochondrial apoptosis by modulating BAK activity.
Opferman et al. (2005) tested MCL1 as an attractive candidate for regulation of hematopoietic stem cell homeostasis that is highly expressed in hematopoietic stem cells and regulated by growth factor signals. Inducible deletion of Mcl1 in mice resulted in ablation of bone marrow. This resulted in the loss of early bone marrow progenitor populations, including hematopoietic stem cells. Moreover, growth factors including stem cell factor (184745) increased transcription of the MCL1 gene and required MCL1 to augment survival of purified bone marrow progenitors. Deletion of MCL1 in other tissues, including liver, did not impair survival. Thus, MCL1 is a critical and specific regulator essential for ensuring the homeostasis of early hematopoietic progenitors.
Maurer et al. (2006) found that Gsk3-alpha (GSK3A; 606784) and -beta (GSK3B; 605004) phosphorylated mouse Mcl1 at a conserved GSK3 phosphorylation site, and this phosphorylation led to increased ubiquitylation and degradation of Mcl1. In mouse pre-B lymphocytic cells, Il3 (147740) withdrawal or Pi3 kinase (see PIK3CG; 601232) inhibition induced phosphorylation of Mcl1, and Akt (see AKT1; 164730) or inhibition of Gsk3 activity prevented Mcl1 phosphorylation. Mcl1 with a mutation of the phosphorylation site showed enhanced stability upon Il3 withdrawal and conferred increased resistance to apoptosis compared with wildtype Mcl1. Maurer et al. (2006) concluded that control of MCL1 stability by GSK3 regulates apoptosis by growth factors, PI3 kinase, and AKT.
Mott et al. (2007) found that MCL1 protein was overexpressed and that miR29B (see MIRN29B1; 610783) was underexpressed in the malignant human cholangiocarcinoma cell line KMCH compared with normal human cholangiocytes. In silico analysis revealed a putative miR29-binding site in the 3-prime UTR of MCL1 mRNA. Enforced expression of miR29B through transfection of the miR29B1 precursor reduced MCL1 protein expression in KMCH cells. This effect was direct, as miR29B negatively regulated expression of an MCL1 3-prime UTR-based reporter construct. Enforced miR29B expression also sensitized cancer cells to TRAIL (TNFSF10; 603598)-mediated apoptotic cell death. Transfection of nonmalignant cells with an miR29B antagonist increased MCL1 levels and reduced TRAIL-mediated apoptosis. Mott et al. (2007) concluded that miR29 is an endogenous regulator of MCL1 protein expression and apoptosis.
Schwickart et al. (2010) showed that the deubiquitinase USP9X (300072) binds to and stabilizes MCL1 and removes the lys48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlated with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increased MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. Schwickart et al. (2010) concluded that their results identified USP9X as a prognostic and therapeutic target and showed that deubiquitinases may stabilize labile oncoproteins in human malignancies.
Vikstrom et al. (2010) investigated the consequences of deleting genes encoding the antiapoptotic molecules Mcl1 and Bcl2l1 from B cells using an inducible system synchronized with expression of activation-induced cytidine deaminase after immunization. This revealed Mcl1 and not Bcl2l1 to be indispensable for the formation and persistence of germinal centers. Limiting Mcl1 expression reduced the magnitude of the germinal center response with an equivalent, but not greater, effect on memory B cell formation and no effect on persistence. Vikstrom et al. (2010) concluded that their results identified Mcl1 as the main antiapoptotic regulator of activated B cell survival and suggested distinct mechanisms controlling survival of germinal center and memory B cells.
Inuzuka et al. (2011) demonstrated that the E3 ubiquitin ligase SCF-FBW7 (a SKP1-cullin-1-F-box complex that contains FBW7 (606278) as the F-box protein) governs cellular apoptosis by targeting MCL1, a prosurvival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase-3 (see 605004). Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis.
Wertz et al. (2011) demonstrated that the prosurvival protein MCL1 is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a posttranslational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumor suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumor cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumor samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Wertz et al. (2011) concluded that their findings suggested that profiling the FBW7 and MCL1 status of tumors, in terms of protein levels, mRNA levels, and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.
Hellmuth and Stemmann (2020) showed that human cells that enter mitosis with already active separase (ESPL1; 604143) rapidly undergo death in mitosis owing to direct cleavage of antiapoptotic MCL1 and BCLXL (600039) by separase. Cleavage not only prevents MCL1 and BCLXL from sequestering proapoptotic BAK (600516), but also converts them into active promoters of death in mitosis. The data strongly suggested that the deadliest cleavage fragment, the C-terminal half of MCL1, forms BAK/BAX (600040)-like pores in the mitochondrial outer membrane. MCL1 and BCLXL are turned into separase substrates only upon phosphorylation by NEK2A (604043). Early mitotic degradation of this kinase is therefore crucial for preventing apoptosis upon scheduled activation of separase in metaphase. Speeding up mitosis by abrogation of the spindle assembly checkpoint (SAC) results in a temporal overlap of the enzymatic activities of NEK2A and separase and consequently in cell death. Hellmuth and Stemmann (2020) proposed that NEK2A and separase jointly check on SAC integrity and eliminate cells that are prone to chromosome missegregation owing to accelerated progression through early mitosis.
Using the methods of somatic cell hybrid analysis and fluorescence in situ hybridization, Craig et al. (1994) mapped MCL1 to 1q21. In the mouse, MCL1-related sequences were mapped to positions on 2 mouse chromosomes, 3 and 5, using haplotype analysis of an interspecific cross. The locus on mouse chromosome 3, Mcl1, was homologous to MCL1 on human chromosome 1; the second locus, Mcl-rs, on mouse chromosome 5, may represent a pseudogene. The proximal long arm of human chromosome 1, where MCL1 is located, is duplicated and/or rearranged in a variety of preneoplastic and neoplastic diseases, including hematologic and solid tumors. Thus, MCL1 is a candidate gene for involvement in cancer.
Rinkenberger et al. (2000) disrupted the Mcl1 locus in murine ES cells to determine the developmental roles of this Bcl2 family member. Deletion of Mcl1 resulted in periimplantation embryonic lethality. Homozygous Mcl1-deficient embryos did not implant in utero, but could be recovered at E3.5 to E4.0. Null blastocysts failed to hatch or attach in vitro, indicating a trophectoderm defect, although the inner cell mass could grow in culture. Of note, homozygous Mcl1-deficient blastocysts showed no evidence of increased apoptosis, but exhibited a delay in maturation beyond the precompaction stage. This model indicates that Mcl1 is essential for preimplantation development and implantation, and suggests that it has a function beyond regulating apoptosis.
Using a Cre/lox system, Opferman et al. (2003) generated mice with conditional Mcl1 deficiency. The mice displayed a profound reduction in B and T lymphocytes after Mcl1 was removed. Differentiation of B lymphocytes was arrested at the pro-B-cell stage, while that of T lymphocytes stopped at the double-negative stage. Peripheral B and T lymphocytes were rapidly deleted. Opferman et al. (2003) noted that this developmental impairment is similar to defects observed in Il7 (146660)- or Il7r (146661)-deficient mice and showed that Il7 induces Mcl1 expression in Rag2 (179616)-deficient thymocytes and in wildtype T lymphocytes. Expression in wildtype T lymphocytes was induced to a lesser extent with Il15 (600554) and still less with Il2 (147680). Adoptive transfer experiments indicated that Mcl1 is required for the maintenance of peripheral B and T cells. Coimmunoprecipitation analysis indicated that Mcl1 binds to the proapoptotic molecule Bim (603827) but not to Bad (603167), both of which are BH3-only members of the BCL2 (151430) family. Opferman et al. (2003) concluded that MCL1 selectively inhibits BIM and is essential both for early lymphoid development and later maintenance of mature lymphocytes.
Bae, J., Leo, C. P., Hsu, S. Y., Hsueh, A. J. W. MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J. Biol. Chem. 275: 25255-25261, 2000. [PubMed: 10837489] [Full Text: https://doi.org/10.1074/jbc.M909826199]
Craig, R. W., Jabs, E. W., Zhou, P., Kozopas, K. M., Hawkins, A. L., Rochelle, J. M., Seldin, M. F., Griffin, C. A. Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease. Genomics 23: 457-463, 1994. [PubMed: 7835896] [Full Text: https://doi.org/10.1006/geno.1994.1523]
Hellmuth, S., Stemmann, O. Separase-triggered apoptosis enforces minimal length of mitosis. Nature 580: 542-547, 2020. [PubMed: 32322059] [Full Text: https://doi.org/10.1038/s41586-020-2187-y]
Inuzuka, H., Shaik, S., Onoyama, I., Gao, D., Tseng, A., Maser, R. S., Zhai, B., Wan, L., Gutierrez, A., Lau, A. W., Xiao, Y., Christie, A. L., Aster, J., Settleman, J., Gygi, S. P., Kung, A. L., Look, T., Nakayama, K. I., DePinho, R. A., Wei, W. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471: 104-109, 2011. [PubMed: 21368833] [Full Text: https://doi.org/10.1038/nature09732]
Kozopas, K. M., Yang, T., Buchan, H. L., Zhou, P., Craig, R. W. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc. Nat. Acad. Sci. 90: 3516-3520, 1993. [PubMed: 7682708] [Full Text: https://doi.org/10.1073/pnas.90.8.3516]
Leu, J. I.-J., Dumont, P., Hafey, M., Murphy, M. E., George, D. L. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nature Cell Biol. 6: 443-450, 2004. [PubMed: 15077116] [Full Text: https://doi.org/10.1038/ncb1123]
Maurer, U., Charvet, C., Wagman, A. S., Dejardin, E., Green, D. R. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Molec. Cell 21: 749-760, 2006. [PubMed: 16543145] [Full Text: https://doi.org/10.1016/j.molcel.2006.02.009]
Mott, J. L., Kobayashi, S., Bronk, S. F., Gores, G. J. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26: 6133-6140, 2007. [PubMed: 17404574] [Full Text: https://doi.org/10.1038/sj.onc.1210436]
Opferman, J. T., Iwasaki, H., Ong, C. C., Suh, H., Mizuno, S., Akashi, K., Korsmeyer, S. J. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307: 1101-1104, 2005. [PubMed: 15718471] [Full Text: https://doi.org/10.1126/science.1106114]
Opferman, J. T., Letai, A., Beard, C., Sorcinelli, M. D., Ong, C. C., Korsmeyer, S. J. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426: 671-676, 2003. [PubMed: 14668867] [Full Text: https://doi.org/10.1038/nature02067]
Rinkenberger, J. L., Horning, S., Klocke, B., Roth, K., Korsmeyer, S. J. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev. 14: 23-27, 2000. [PubMed: 10640272]
Schwickart, M., Huang, X., Lill, J. R., Liu, J., Ferrando, R., French, D. M., Maecker, H., O'Rourke, K., Bazan, F., Eastham-Anderson, J., Yue, P., Dornan, D., Huang, D. C. S., Dixit, V. M. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463: 103-107, 2010. [PubMed: 20023629] [Full Text: https://doi.org/10.1038/nature08646]
Vikstrom, I., Carotta, S., Luthje, K., Peperzak, V., Jost, P. J., Glaser, S., Busslinger, M., Bouillet, P., Strasser, A., Nutt, S. L., Tarlinton, D. M. Mcl-1 is essential for germinal center formation and B cell memory. Science 330: 1095-1099, 2010. [PubMed: 20929728] [Full Text: https://doi.org/10.1126/science.1191793]
Wertz, I. E., Kusam, S., Lam, C., Okamoto, T., Sandoval, W., Anderson, D. J., Helgason, E., Ernst, J. A., Eby, M., Liu, J., Belmont, L. D., Kaminker, J. S., and 15 others. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471: 110-114, 2011. Note: Erratum: Nature 475: 122 only, 2011. [PubMed: 21368834] [Full Text: https://doi.org/10.1038/nature09779]