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 [+]

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 [+]

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
mcl1a	orthology	Zebrafish
mcl1b	orthology	Zebrafish
NP_001026091.1	paralogy	Chicken
BCLX_CHICK	paralogy	Chicken
NP_990197.1	paralogy	Chicken
XR_024448.1	paralogy	Chimpanzee
BCL2A1	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
BCL2A1	paralogy	Human
BAK1	paralogy	Human
BAK1	paralogy	Lyzard
BAK1	paralogy	Macaca
BCL2A1	paralogy	Macaca
BAX	paralogy	Medaka
O_latipes_ENSORLP00000015978	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

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

Information from other databases [+]

Gene related links:

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

Protein related links:

Uniprot protein info: Q07820
PIR protein info: Q07820
Protein interactions from IntAct: Q07820

Gene and disease information from OMIM: (For a full disease description table, click here.)

OMIM gene information: 159552
OMIM disease information:

Other links

entrezgene: 4170
refseq_dna: NM_182763
refseq_dna: NM_021960
refseq_peptide: NP_877495
refseq_peptide: NP_068779

Click on [?] for more information.