MCL1

Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.^[5][6]

MCL1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KBW, 2MHS, 2NL9, 2NLA, 2PQK, 3D7V, 3IO9, 3KJ0, 3KJ1, 3KJ2, 3KZ0, 3MK8, 3PK1, 3TWU, 3WIX, 3WIY, 4BPI, 4BPJ, 4HW2, 4HW3, 4HW4, 4OQ5, 4OQ6, 4WGI, 4WMR, 4WMS, 4WMT, 4WMU, 4WMV, 4WMW, 4WMX, 4ZBF, 4ZBI, 5FDO, 5FDR, 5FC4, 5C3F
Identifiers
Aliases	MCL1, BCL2L3, EAT, MCL1-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, myeloid cell leukemia 1, BCL2 family apoptosis regulator, BCL2 family apoptosis regulator, MCL1 apoptosis regulator, BCL2 family member
External IDs	OMIM: 159552; MGI: 101769; HomoloGene: 7413; GeneCards: MCL1; OMA:MCL1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.2 Start 150,560,895 bp[1] End 150,579,738 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 F2.1|3 40.74 cM Start 95,566,099 bp[2] End 95,570,487 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in visceral pleura parietal pleura mucosa of urinary bladder saphenous vein Epithelium of choroid plexus epithelium of nasopharynx mononuclear cell monocyte cardia gallbladder Top expressed in otic placode saccule stroma of bone marrow mesenteric lymph nodes granulocyte left colon conjunctival fornix blood right lung lobe left lung More reference expression data BioGPS More reference expression data
Gene ontology Molecular function BH3 domain binding protein binding protein heterodimerization activity protein homodimerization activity protein transmembrane transporter activity Cellular component cytoplasm integral component of membrane membrane Bcl-2 family protein complex nucleoplasm mitochondrial outer membrane mitochondrial matrix mitochondrion nucleus cytosol Biological process regulation of apoptotic process cell differentiation response to cytokine cellular homeostasis multicellular organism development positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway apoptotic mitochondrial changes extrinsic apoptotic signaling pathway in absence of ligand cell fate determination regulation of response to DNA damage stimulus negative regulation of extrinsic apoptotic signaling pathway in absence of ligand negative regulation of anoikis apoptotic process negative regulation of apoptotic process protein transmembrane transport negative regulation of autophagy intrinsic apoptotic signaling pathway in response to DNA damage negative regulation of intrinsic apoptotic signaling pathway cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4170 17210 Ensembl ENSG00000143384 ENSMUSG00000038612 UniProt Q07820 P97287 RefSeq (mRNA) NM_182763 NM_001197320 NM_021960 NM_008562 RefSeq (protein) NP_001184249 NP_068779 NP_877495 NP_032588 Location (UCSC) Chr 1: 150.56 – 150.58 Mb Chr 3: 95.57 – 95.57 Mb PubMed search [3] [4]
Wikidata
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Function

The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. The longer gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene product (isoform 2) promotes apoptosis and is death-inducing.^[7] The protein MCL1 has a very short biological half-life of only 20–30 minutes.^[8]

The loss of MCL1 has a more dramatic impact than the loss of any other anti-apoptotic member of the Bcl-2 family. Loss of the Mcl-1 gene results in embryo death when the embryo is only around 3.5 days old, before it has even implanted. Conditional deletion of Mcl-1 depletes a wide variety of cells, including hematopoietic stem cells, B cell–committed progenitors, T cell–committed progenitors, antibody-secreting plasma cells, cardiac muscle cells, and neurons.^[8] Deletion of Mcl-1 in hepatocytes causes apoptosis and aberrant polyploidization but improves liver regeneration after surgery.^[9][10] MCL1 works synergistically with p53 in protecting liver from injury, fibrosis and cancer.^[11]

MCL1 also has a role in the cell's energy production, working in the intermitochondrial space.^[8]

Clinical significance

Omacetaxine mepesuccinate (a drug approved for the treatment for chronic myelogenous leukemia) and Seliciclib^[12] (which is under investigation as a potential multiple myeloma treatment) both act in part by inhibiting synthesis of Mcl-1. MCL1 has been identified as a resistance factor for BCL-2 inhibitor venetoclax in lymphoma cells. Therefore, new strategies of combining BCL-2 and MCL1 inhibitors are currently under clinical trials for several tumor types.^[13]

Interactions

MCL1 has been shown to promiscuously interact with:

• BAK1,^{[14][15][16][17]}
• BCL2L11, commonly called BIM,^{[17][18][19][20]}
• BID,^[16][18]
• BAD,^[18][21]
• DAD1,^[22]
• PMAIP1, commonly called NOXA,^[15][18][23]
• PCNA,^[24]
• PUMA,^[25]
• TCTP^[26] and
• TNKS^[27]

See also

• Bcl-2
• Bcl-xL