MCL1 (Homo sapiens)
Description [+]
- Synonyms: MCL1, BCL2L3
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
- Short gene description: Induced myeloid leukemia cell differentiation protein Mcl-1 (Bcl-2-related protein EAT/mcl1)(mcl1/EAT) [Source:UniProtKB/Swiss-Prot;Acc:Q07820]
- Family: Bcl-2 family : multidomain Bcl-2
- Process: apoptosis,
- Pathways: intrinsic pathway, pre-mitochondrial signaling events,
- Criteria: manually curated
- Curator comment:
- Mouse ortholog(s): Mcl1
- WIKI: MCL1-H_sapiens
References [+]
- MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2.
- Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW
- During their lifespan, immature cells normally pass through sequential transitions to a differentiated state and eventually undergo cell death. This progression is aberrant in cancer, although the transition to differentiation can be reestablished in inducible leukemia cell lines. This report describes a gene, MCL1, that we isolated from the ML-1 human myeloid leukemia cell line during phorbol ester-induced differentiation along the monocyte/macrophage pathway. Our results demonstrate that expression of MCL1 increases 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). They further show that MCL1 has sequence similarity to BCL2, a gene involved in normal lymphoid development and in lymphomas with the t(14;18) chromosome translocation. MCL1 and BCL2 do not fall into previously known gene families. BCL2 differs from many oncogenes in that it inhibits programmed cell death, promoting viability rather than proliferation; this parallels the association of MCL1 with the programming of differentiation and concomitant maintenance of viability but not proliferation. Thus, in contrast to proliferation-associated genes, expression of MCL1 and BCL2 relates to the programming of differentiation and cell viability/death. The discovery of MCL1 broadens our perspective on an emerging MCL1/BCL2 gene family and will allow further comparison with oncogene families. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3516-20.
- MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain.
- Bae J, Leo CP, Hsu SY, Hsueh AJ
- MCL-1 (myeloid cell leukemia-1) is an antiapoptotic BCL-2 family protein discovered as an early induction gene during myeloblastic leukemia cell differentiation. This survival protein has the BCL-2 homology (BH) domains 1, 2, and 3 and a C-terminal transmembrane region. We identified a short splicing variant of the MCL-1 mRNA in the human placenta encoding a protein, termed MCL-1 short (MCL-1S), with an altered C terminus as compared with the full-length MCL-1 long (MCL-1L), leading to the loss of BH1, BH2, and the transmembrane domains. Analysis of the human MCL-1 gene indicated that MCL-1S results from the splicing out of exon 2 during mRNA processing. MCL-1S, unlike MCL-1L, does not interact with diverse proapoptotic BCL-2-related proteins in the yeast two-hybrid system. In contrast, MCL-1S dimerizes with MCL-1L in the yeast assay and coprecipitates with MCL-1L in transfected mammalian cells. Overexpression of MCL-1S induces apoptosis in transfected Chinese hamster ovary cells, and the MCL-1S action was antagonized by the antiapoptotic MCL-1L. Thus, the naturally occurring MCL-1S variant represents a new proapoptotic BH3 domain-only protein capable of dimerizing with the antiapoptotic MCL-1L. The fate of MCL-1-expressing cells could be regulated through alternative splicing mechanisms and interactions of the resulting anti- and proapoptotic gene products. J Biol Chem. 2000 Aug 18;275(33):25255-61.
- References from Mouse ortholog(s):
- Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions.
- Zhou P, Qian L, Kozopas KM, Craig RW
- Mcl-1 is a member of the Bcl-2 family that was identified based on increased expression in myeloblastic leukemia cells undergoing differentiation. Mcl-1 was previously found to be similar to Bcl-2 in causing a delay in apoptotic cell death in Chinese hamster ovary cells. The work described here was aimed at determining whether Mcl-1 could also exert such an effect in hematopoietic cells, because endogenous Mcl-1 expression is prominent in the hematopoietic system. A further aim was to assess the effects of Mcl-1 in cells exposed to a variety of cytotoxic stimuli, because Bcl-2 is known to have a broad spectrum of activity. To approach these aims, FDC-P1 murine myeloid progenitor cells were transfected with vectors driving either constitutive or inducible expression of Mcl-1. The introduced Mcl-1 gene was found to cause a prolongation of viability under various conditions that cause apoptotic cell death, including exposure to cytotoxic agents (the chemotherapeutic drug etoposide, calcium ionophore, or UV irradiation) and the withdrawal of required growth factors. In addition, Mcl-1 was found to interact with Bax, a member of the Bcl-2 family that promotes cell death as a homodimer but that can heterodimerize with Bcl-2 to promote cell viability. Although Mcl-1 prolonged cell viability, it did not prevent eventual cell death upon continuous exposure to a cytotoxic agent. Prolongation of viability was maximal when expression of Mcl-1 was induced before the application of the apoptotic stimulus, although some increase occurred if Mcl-1 was induced shortly thereafter and before overt apoptosis. Taken as a whole, these findings provide further parallels between Mcl-1 and Bcl-2, showing that Mcl-1 can interact with Bax in hematopoietic FDC-P1 cells and can prolong cell viability under a variety of cytotoxic conditions. Blood. 1997 Jan 15;89(2):630-43.
- Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.
- Vick B, Weber A, Urbanik T, Maass T, Teufel A, Krammer PH, Opferman JT, Schuchmann M, Galle PR, Schulze-Bergkamen H
- Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocytes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1(flox/flox)-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1(flox/flox)-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1(flox/flox)-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction. Hepatology. 2009 Feb;49(2):627-36.
Structure & Sequence [+]
Pfam domains:
(Pfam is a large collection of protein families.)
Source | Domain Name | Start | End |
---|---|---|---|
PFAM A | Bcl-2 | 213 | 312 |
Protein sequence [+]
MCL1 | Homo sapiens | 9606 | length:350
MFGLKRNAVIGLNLYCGGAGLGAGSGGATRPGGRLLATEKEASARREIGGGEAGAVIGGS
AGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIM
SPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLE
IISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNE
DDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVR
TKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR
AGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIM
SPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLE
IISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNE
DDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVR
TKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR
Structure links:
- Smartdomain prediction information: SM00337
- Prosite motif and domain information: PS01259
- Prosite motif and domain information: PS01080
- Prosite motif and domain information: PS01258
- Profile motif and domain profile information: PS50062
- Interpro domain information: Q07820
- PFAM domain and domain family information: Q07820
- Protein 3D structures from PDB: 2NLA 2NL9
Evolution [+]
View protein alignment and tree with Jalview:  
Explore tree at phylomeDB:   Click here.
Homologs list [+]
Name | Relationship | Species |
---|---|---|
MCL1 | orthology | Chimpanzee |
NP_001092676.1 | orthology | Cow |
IPI00908204.1 | orthology | Cow |
MCL1_CANFA | orthology | Dog |
MCL1 | orthology | Fugu |
MCL1 | orthology | Gasterosteus |
MCL1 | orthology | Gorilla |
MCL1 | orthology | Horse |
MCL1 | orthology | Lyzard |
MCL1 | orthology | Macaca |
MCL1 | orthology | Medaka |
MCL1 | orthology | Monodelphis |
Mcl1 | orthology | Mouse |
MCL1 | orthology | Orangutan |
MCL1 | orthology | Rabbit |
RGD1562809_predicted | orthology | Rat |
MCL1 | orthology | Tetraodon |
MCL1 | orthology | Xenopus |
mcl1b | orthology | Zebrafish |
mcl1a | orthology | Zebrafish |
NP_001026091.1 | paralogy | Chicken |
BCLX_CHICK | paralogy | Chicken |
NP_990197.1 | paralogy | Chicken |
BCL2A1 | paralogy | Chimpanzee |
XR_024448.1 | paralogy | Chimpanzee |
C_intestinalis_ENSCINP00000024813 | paralogy | Ciona |
B2LA1_BOVIN | paralogy | Cow |
NP_001071386.1 | paralogy | Cow |
BCL2A1 | paralogy | Dog |
GNB5 (2 of 2) | paralogy | Fugu |
BCL2L1 (1 of 6) | paralogy | Fugu |
G_aculeatus_ENSGACP00000021797 | paralogy | Gasterosteus |
BAK1 | paralogy | Gorilla |
BAK1 | paralogy | Horse |
BAK1 | paralogy | Human |
BCL2A1 | paralogy | Human |
BAK1 | paralogy | Lyzard |
BAK1 | paralogy | Macaca |
BCL2A1 | paralogy | Macaca |
O_latipes_ENSORLP00000015978 | paralogy | Medaka |
BAX | paralogy | Medaka |
BCL2A1 | paralogy | Monodelphis |
BAK1 | paralogy | Monodelphis |
Bcl2 | paralogy | Mouse |
BCL2A1 | paralogy | Orangutan |
P_pygmaeus_ENSPPYP00000006150 | paralogy | Orangutan |
Bcl2 | paralogy | Rat |
BCL2L1 (1 of 3) | paralogy | Tetraodon |
T_nigroviridis_ENSTNIP00000002209 | paralogy | Tetraodon |
T_nigroviridis_ENSTNIP00000017211 | paralogy | Tetraodon |
BCL2A1 | paralogy | Zebra finch |
baxa | paralogy | Zebrafish |
bcl2 | paralogy | Zebrafish |
D_rerio_ENSDARP00000037180 | paralogy | Zebrafish |
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Gene Ontology [+]
GO id | Name | Ontology type | Evidence |
---|---|---|---|
GO:0042981 | regulation of apoptosis | biological_proccess | IEA |
GO:0034097 | response to cytokine stimulus | biological_proccess | IDA |
GO:0007275 | multicellular organismal development | biological_proccess | IEA |
GO:0030154 | cell differentiation | biological_proccess | IEA |
GO:0006916 | anti-apoptosis | biological_proccess | TAS |
GO:0001709 | cell fate determination | biological_proccess | NAS |
GO:0019725 | cellular homeostasis | biological_proccess | NAS |
GO:0046982 | protein heterodimerization activity | mollecular_function | IPI |
GO:0005515 | protein binding | mollecular_function | IDA |
GO:0015266 | protein channel activity | mollecular_function | TAS |
GO:0005515 | protein binding | mollecular_function | IEA |
GO:0005739 | mitochondrion | cell_component | IDA |
GO:0016020 | membrane | cell_component | IDA |
GO:0005634 | nucleus | cell_component | IEA |
GO:0016021 | integral to membrane | cell_component | IEA |
GO:0005654 | nucleoplasm | cell_component | IEA |
GO:0005737 | cytoplasm | cell_component | TAS |
GO:0005741 | mitochondrial outer membrane | cell_component | TAS |
Check GO Evidence Codes here
miRNAs [+]
miRNA | Regulation | Description | Pubmed |
---|---|---|---|
hsa-miR-15a/hsa-miR-16 | overexpression | We selected genes that were low in miR-15/16 high-expressor CLLs and high in miR-15/16 low-expressor CLLs, which were intersected with genes down-regulated in MEG-01 cells after transfection with pRS15/16. A signature of 60 genes (70 probes) emerged (Table 4 and SI Table 11). | Ref. |
hsa-miR-193a-3p | overexpression by miRNA precursor transfection | In addition, down-regulation of MCL1, an antiapoptotic Bcl-2 family member, was also detected in all OSCC cell lines transfected with miR-193a compared with negative control dsRNA | Ref. |
hsa-miR-29b | overexpression by miRNA precursor transfection | Immunofluorescence demonstrated decreased Mcl-1 reactivity in mir-29b-transfected cells (Figure 3c). | Ref. |
hsa-miR-29b | overexpression by miRNA precursor transfection | Similarly, KMCH cells transfected with the mir-29b expression plasmid p29b had reduced Mcl-1 protein by Western blot (Figure 3d). | Ref. |
Curated Isoforms [+]
Transcript | Translation |
---|---|
OTTHUMT00000084402 * | OTTHUMP00000032794 * |
OTTHUMT00000084403 | OTTHUMP00000032795 |
OTTHUMT00000087243 |
Info from The Vertebrate Genome Annotation (VEGA) database.
(*) Canonical transcript and translation forms.
Information from other databases [+]
- Gene info from HGNC [?] :6943
- Gene related info from GeneCards [?] : MCL1
- Ensembl genome browser [?] : ENSG00000143384
- Expression info from Arrayexpress [?] : ENSG00000143384
- Protein expression from Protein Atlas: [?] ENSG00000143384
- Community gene edition from Wikigenes: [?] 4170
- OMIM gene information: 159552
- OMIM disease information:
Click on [?] for more information.