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
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.2 Start 150,574,551 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 95,658,788 bp[2] End 95,663,176 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • BH3 domain binding • GO:0001948 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 • cell 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: 150.57 – 150.58 Mb	Chr 3: 95.66 – 95.66 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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]

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 (CML)) and Seliciclib [9] (which is under investigation as a potential multiple myeloma treatment) both act in part by inhibiting synthesis of Mcl-1.

Interactions

MCL1 has been shown to interact with:

• BAK1,[10][11][12][13]
• BCL2L11,[13][14][15]
• BID,[12][14]
• BAD,[14][16]
• DAD1,[17]
• PMAIP1,[11][14]
• PCNA,[18]
• TCTP[19] and
• TNKS[20]

See also

• Bcl-2
• Bcl-xL

References

1. GRCh38: Ensembl release 89: ENSG00000143384 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038612 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW (May 1993). "MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2". Proc Natl Acad Sci U S A. 90 (8): 3516–20. doi:10.1073/pnas.90.8.3516. PMC 46331. PMID 7682708.
6. Craig RW, Jabs EW, Zhou P, Kozopas KM, Hawkins AL, Rochelle JM, Seldin MF, Griffin CA (February 1995). "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 (2): 457–63. doi:10.1006/geno.1994.1523. PMID 7835896.
7. "Entrez Gene: MCL1 myeloid cell leukemia sequence 1 (BCL2-related)".
8. Kelly GL, Strasser A (March 2020). "Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy". Annual Review of Cancer Biology. 4: 299–313. doi:10.1146/annurev-cancerbio-030419-033510.
9. MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR (2005). "Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1". Cancer Research. 65 (12): 5399–5407. doi:10.1158/0008-5472.CAN-05-0233. PMID 15958589.
10. Leu JI, Dumont P, Hafey M, Murphy ME, George DL (May 2004). "Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex". Nat. Cell Biol. 6 (5): 443–50. doi:10.1038/ncb1123. PMID 15077116.
11. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC (June 2005). "Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins". Genes Dev. 19 (11): 1294–305. doi:10.1101/gad.1304105. PMC 1142553. PMID 15901672.
12. Weng C, Li Y, Xu D, Shi Y, Tang H (March 2005). "Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells". J. Biol. Chem. 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID 15637055.
13. Bae J, Leo CP, Hsu SY, Hsueh AJ (August 2000). "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 (33): 25255–61. doi:10.1074/jbc.M909826199. PMID 10837489.
14. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (February 2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Mol. Cell. 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. PMID 15694340.
15. Hsu SY, Lin P, Hsueh AJ (September 1998). "BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members". Mol. Endocrinol. 12 (9): 1432–40. doi:10.1210/mend.12.9.0166. PMID 9731710.
16. Bae J, Hsu SY, Leo CP, Zell K, Hsueh AJ (October 2001). "Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis". Apoptosis. 6 (5): 319–30. doi:10.1023/A:1011319901057. PMID 11483855.
17. Makishima T, Yoshimi M, Komiyama S, Hara N, Nishimoto T (September 2000). "A subunit of the mammalian oligosaccharyltransferase, DAD1, interacts with Mcl-1, one of the bcl-2 protein family". J. Biochem. 128 (3): 399–405. doi:10.1093/oxfordjournals.jbchem.a022767. PMID 10965038.
18. Fujise K, Zhang D, Liu J, Yeh ET (December 2000). "Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen". J. Biol. Chem. 275 (50): 39458–65. doi:10.1074/jbc.M006626200. PMID 10978339.
19. Liu H, Peng HW, Cheng YS, Yuan HS, Yang-Yen HF (April 2005). "Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP". Mol Cell Biol. 25 (8): 3117–26. doi:10.1128/MCB.25.8.3117-3126.2005. PMC 1069602. PMID 15798198.
20. Bae J, Donigian JR, Hsueh AJ (February 2003). "Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis". J. Biol. Chem. 278 (7): 5195–204. doi:10.1074/jbc.M201988200. PMID 12475993.

Further reading

• Yang-Yen HF (2006). "Mcl-1: a highly regulated cell death and survival controller". J. Biomed. Sci. 13 (2): 201–4. doi:10.1007/s11373-005-9064-4. PMID 16456709.

External links

• Overview of all the structural information available in the PDB for UniProt: Q07820 (Induced myeloid leukemia cell differentiation protein Mcl-1) at the PDBe-KB.