MCL1

Official Full Name

MCL1 apoptosis regulator, BCL2 family member

Organism

Homo sapiens

GeneID

4170

Background

This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010]

Synonyms

TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1/EAT;

Bio Chemical Class

B-cell lymphoma Bcl-2

Protein Sequence

MFGLKRNAVIGLNLYCGGAGLGAGSGGATRPGGRLLATEKEASARREIGGGEAGAVIGGSAGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIMSPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLEIISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNEDDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVRTKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR

Open

Disease

Acute myeloid leukaemia, Asthma, Malignant haematopoietic neoplasm, Mature B-cell lymphoma, Melanoma, Multiple myeloma, Rheumatoid arthritis, Solid tumour/cancer, Trematode disease

Approved Drug

1 +

Clinical Trial Drug

7 +

Discontinued Drug

2 +

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Detailed Information

The MCL-1 gene was first discovered as an early induction gene in the differentiation of the monocyte/macrophage pathway after induction of the human ML-1 myeloid leukemia cell line with phorbol ester. MCL-1L has a BH1 - 3 domain but lacks the BH4 domain of Bcl - 2 and Bcl - XL amino terminus. Like many other Bcl-2 family proteins, MCL-1 contains a transmembrane (TM) domain at the carbon terminus that functions to localize MCL-1 in different intracellular membranes, particularly the mitochondrial outer membrane. This localization is consistent with the function of MCL-1, which allows MCL-1 to regulate important responses in mitochondria during apoptosis. Moreover, and MCL-1 is also found in other cell inner membranes.

Distribution of MCL-1

MCL-1 expression can be detected in many cells, and high expression of MCL-1 can be detected in the apical layer of epithelial cells with strong differentiation ability, such as prostate, breast, colon and lung epithelium, while Bcl-2 is highly expressed on the substrate of cell layer. In addition, the endometrial epithelium, gastric epithelium, intestinal epithelium, respiratory epithelium, neuroendocrine cells (such as adrenocortical cells, sympathetic neurons, some islet cells, and spermatogenic cells of the testes) have expression of the MCL-1 gene. In the lymphatic system, MCL-1 is abundantly expressed in the B cell region of the germinal center, while Bcl-2 is mainly expressed in the cloned B cells of the nest. This difference in distribution suggests that MCL-1 and Bcl-2 have different roles in the regulation of apoptosis.

MCL1 Figure 1. Schematic representation of molecular mechanism of combination therapy of BEZ235 and ABT263. (Li, H. 2018)

Many survival and differentiation signals induce MCL-1 expression, such as cytokines and growth factors, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K) and tyrosine kinase/signal induction and transcriptional activators (STAT) dependent pathways can stimulate MCL-1 transcription by specific transcription factor response elements in the MCL-1 promoter. Direct phosphorylation of MCL-1 also plays an important role in the regulation of MCL-1 expression and function.

In contrast to the anti-apoptotic Bcl-2 and Bcl-XL proteins, MCL-1 is down-regulated during many apoptosis processes. Caspase-mediated breakdown of MCL-1 may be the main cause of down-regulation of its expression. For example, Caspase3 can cleave MCL-1 in two aspartate residues of human MCL-1 protein, ASP127 and ASP157.

MCL-1 and Tumor

Studies in lung cancer have shown that MCL-1 protein is abundantly expressed in lung cancer cells and that MCL-1 expression is significantly elevated in non-small cell lung cancer (NSCLC) cells directly derived from patients compared with nearby normal lung tissues. The addition of epidermal growth factor (EGF) stimulates MCL-1 expression in a Src-kinase-activated form, as Src's drug inhibitors prevent EGF from up-regulating MCL-1. Further studies have shown that MCL-1 antisense oligonucleotides reduce the level of MCL-1, and can make lung cancer cells more sensitive to apoptosis induced by cisplatin, etoposide, and docetaxel. Stably overexpress MCL-1 lung cancer cells have increased viability after exposure to chemotherapeutic drugs. Decreased levels of MCL-1 can sensitize lung cancer cells to cytotoxic drugs and ionizing radiation-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising drug for the treatment of cancer including cholangiocarcinoma. However, many cholangiocarcinoma cells are resistant to TRAIL-mediated apoptosis. Studies on TRAIL-induced apoptosis-resistant cholangiocarcinoma cell lines revealed that only MCL-1 was overexpressed in the cell line of Bcl-2 protein family Bcl-2, Bcl-xL and MCL-1. The expression of Bcl-2, Bcl-xL and MCL-1 was reduced by small interfering RNA (siRNA) technology, and only MCL-1 small interfering RNA (Mcl-1 - shRNA) made cells sensitive to TRAIL-mediated apoptosis.

References:

Li, H. , Liu, L. , Chang, H. , Zou, Z. , & Xing, D. . (2018). Downregulation of mcl-1 and upregulation of puma using mtor inhibitors enhance antitumor efficacy of bh3 mimetics in triple-negative breast cancer. Cell Death & Disease, 9(2), 137.
Willis, D. N. , Adams, J. R. , Naik, E. , Wei, A. , Huang, C. , & Dewson, G. , et al. (2005). Proapoptotic bak is sequestered by mcl-1 and bcl-xl, but not bcl-2, until displaced by bh3-only proteins. GENES & DEVELOPMENT, 19(11), 1294-305.
Luedtke, D. A. , Niu, X. , Pan, Y. , Zhao, J. , Liu, S. , & Edwards, H. , et al. (2017). Inhibition of mcl-1 enhances cell death induced by the bcl-2-selective inhibitor abt-199 in acute myeloid leukemia cells. Signal Transduction and Targeted Therapy, 2, 17012.

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