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Gene Review

MCL1  -  myeloid cell leukemia 1

Homo sapiens

Synonyms: BCL2L3, Bcl-2-like protein 3, Bcl-2-related protein EAT/mcl1, Bcl2-L-3, EAT, ...
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Disease relevance of MCL1


High impact information on MCL1


Chemical compound and disease context of MCL1


Biological context of MCL1

  • 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 [1].
  • Thus, in contrast to proliferation-associated genes, expression of MCL1 and BCL2 relates to the programming of differentiation and cell viability/death [1].
  • Therefore, MCL1 may be involved in the inhibitory effect of VEGF on apoptotic cell death [15].
  • This finding prompted us to investigate whether MCL1, in addition to its anti-apoptotic function, has an effect on cell cycle progression [16].
  • Using a robust small interfering RNA (siRNA)-mediated gene silencing system developed in our laboratory, we analyzed the cytoprotective effects of fortilin and MCL1 together and apart in U2OS cell lines exposed to 5-fluorouracil (5-FU) in both monoclonal and polyclonal cell populations [17].

Anatomical context of MCL1


Associations of MCL1 with chemical compounds

  • Antiapoptotic protein partners fortilin and MCL1 independently protect cells from 5-fluorouracil-induced cytotoxicity [17].
  • A bromodeoxyuridine uptake assay showed that the overexpression of MCL1 significantly inhibited the cell cycle progression through the S-phase [16].
  • In addition, other agents that markedly increased ERK phosphorylation (lipopolysaccharide, okadaic acid) also increased MCL1 expression [21].
  • BH3-ligand regulates access of MCL-1 to its E3 ligase [22].
  • 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 [23].

Physical interactions of MCL1


Regulatory relationships of MCL1

  • Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor [15].
  • MCL1 is a viability-promoting member of the BCL2 family that exhibits a rapid increase in expression in response to specific differentiation- and apoptosis-inducing stimuli [21].
  • Expression of the antiapoptotic MCL1 gene product is regulated by a mitogen activated protein kinase-mediated pathway triggered through microtubule disruption and protein kinase C [21].
  • Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex [24].

Other interactions of MCL1

  • Induction of BCL2 family member MCL1 as an early response to DNA damage [25].
  • Upregulated genes at both time-points were IL1B, CD14 and MCL1 [26].
  • The increase in expression of MCL1 was further studied using a panel of human cell lines that includes cells containing or not containing alterations in p53 as well as cells sensitive or insensitive to the apoptosis-inducing effects of DNA damage [25].
  • Baseline levels of message were detected for 3 ced-3 (CPP32, Ich-1 and ICE) and 4 ced-9 homologs (bcl-x, MCL1, bcl-2 and bax) in the frontal cortex [27].
  • A multiple pathway model is now presented, which demonstrates that MCL1 can undergo distinct phosphorylation events - mediated through separate signaling processes and involving different target sites - in cells that remain viable in the presence of TPA versus cells destined to die upon exposure to taxol or okadaic acid [20].

Analytical, diagnostic and therapeutic context of MCL1

  • The intracellular localization of fortilin was predominantly nuclear and identical to that of MCL1, as shown by immunostaining and confocal microscopy analysis [19].
  • The disease-free survival rate was significantly higher in patients with MCL1 levels below the median level (P = 0.007) [4].
  • Immunofluorescence assay showed that hyphal bodies are covered by the N-terminal domains of MCL1 [28].
  • PATIENTS AND METHODS: Between January 1997 and January 1998, 131 patients with newly diagnosed MCL (MCL1; n = 34) and previously treated MCL (MCL2; n = 40), IMC (n = 28), and SLL (n = 29) received rituximab 375 mg/m(2)/wk for 4 weeks via intravenous infusion [29].
  • Using quantitative Western blotting we have determined the level of expression of BCL-2, BAX, MCL-1, and BCL-X in lymphoblasts from 47 children with ALL (33 at presentation only, 4 at relapse only, and 10 at both presentation and on relapse) [30].


  1. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Kozopas, K.M., Yang, T., Buchan, H.L., Zhou, P., Craig, R.W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  2. 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. Craig, R.W., Jabs, E.W., Zhou, P., Kozopas, K.M., Hawkins, A.L., Rochelle, J.M., Seldin, M.F., Griffin, C.A. Genomics (1994) [Pubmed]
  3. An MCL1-overexpressing Burkitt lymphoma subline exhibits enhanced survival on exposure to serum deprivation, topoisomerase inhibitors, or staurosporine but remains sensitive to 1-beta-D-arabinofuranosylcytosine. Vrana, J.A., Bieszczad, C.K., Cleaveland, E.S., Ma, Y., Park, J.P., Mohandas, T.K., Craig, R.W. Cancer Res. (2002) [Pubmed]
  4. High expression of MCL1 gene related to vascular endothelial growth factor is associated with poor outcome in non-Hodgkin's lymphoma. Kuramoto, K., Sakai, A., Shigemasa, K., Takimoto, Y., Asaoku, H., Tsujimoto, T., Oda, K., Kimura, A., Uesaka, T., Watanabe, H., Katoh, O. Br. J. Haematol. (2002) [Pubmed]
  5. Lentiviral (HIV)-based RNA interference screen in human B-cell receptor regulatory networks reveals MCL1-induced oncogenic pathways. Ruiz-Vela, A., Aggarwal, M., de la Cueva, P., Treda, C., Herreros, B., Martín-Pérez, D., Dominguez, O., Piris, M.A. Blood (2008) [Pubmed]
  6. Human papillomavirus type 16/18 up-regulates the expression of interleukin-6 and antiapoptotic Mcl-1 in non-small cell lung cancer. Cheng, Y.W., Lee, H., Shiau, M.Y., Wu, T.C., Huang, T.T., Chang, Y.H. Clin. Cancer Res. (2008) [Pubmed]
  7. BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Gélinas, C., White, E. Genes Dev. (2005) [Pubmed]
  8. DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Cuconati, A., Mukherjee, C., Perez, D., White, E. Genes Dev. (2003) [Pubmed]
  9. Induction of mcl1/EAT, Bcl-2 related gene, by retinoic acid or heat shock in the human embryonal carcinoma cells, NCR-G3. Umezawa, A., Maruyama, T., Inazawa, J., Imai, S., Takano, T., Hata, J. Cell Struct. Funct. (1996) [Pubmed]
  10. The MUC1 SEA module is a self-cleaving domain. Levitin, F., Stern, O., Weiss, M., Gil-Henn, C., Ziv, R., Prokocimer, Z., Smorodinsky, N.I., Rubinstein, D.B., Wreschner, D.H. J. Biol. Chem. (2005) [Pubmed]
  11. Dileucine and YXXL motifs in the cytoplasmic tail of the bovine leukemia virus transmembrane envelope protein affect protein expression on the cell surface. Novakovic, S., Sawai, E.T., Radke, K. J. Virol. (2004) [Pubmed]
  12. Hetero-assembly between all-L- and all-D-amino acid transmembrane domains: forces involved and implication for inactivation of membrane proteins. Sal-Man, N., Gerber, D., Shai, Y. J. Mol. Biol. (2004) [Pubmed]
  13. Downregulation of the antiapoptotic MCL-1 protein and apoptosis in MA-11 breast cancer cells induced by an anti-epidermal growth factor receptor-Pseudomonas exotoxin a immunotoxin. Andersson, Y., Juell, S., Fodstad, Ø. Int. J. Cancer (2004) [Pubmed]
  14. Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43-9006)-induced TRAIL sensitization. Meng, X.W., Lee, S.H., Dai, H., Loegering, D., Yu, C., Flatten, K., Schneider, P., Dai, N.T., Kumar, S.K., Smith, B.D., Karp, J.E., Adjei, A.A., Kaufmann, S.H. J. Biol. Chem. (2007) [Pubmed]
  15. Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor. Katoh, O., Takahashi, T., Oguri, T., Kuramoto, K., Mihara, K., Kobayashi, M., Hirata, S., Watanabe, H. Cancer Res. (1998) [Pubmed]
  16. Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen. Fujise, K., Zhang, D., Liu, J., Yeh, E.T. J. Biol. Chem. (2000) [Pubmed]
  17. Antiapoptotic protein partners fortilin and MCL1 independently protect cells from 5-fluorouracil-induced cytotoxicity. Graidist, P., Phongdara, A., Fujise, K. J. Biol. Chem. (2004) [Pubmed]
  18. Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP. Balakrishnan, K., Stellrecht, C.M., Genini, D., Ayres, M., Wierda, W.G., Keating, M.J., Leoni, L.M., Gandhi, V. Blood (2005) [Pubmed]
  19. Physical and functional interaction between myeloid cell leukemia 1 protein (MCL1) and Fortilin. The potential role of MCL1 as a fortilin chaperone. Zhang, D., Li, F., Weidner, D., Mnjoyan, Z.H., Fujise, K. J. Biol. Chem. (2002) [Pubmed]
  20. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Domina, A.M., Vrana, J.A., Gregory, M.A., Hann, S.R., Craig, R.W. Oncogene (2004) [Pubmed]
  21. Expression of the antiapoptotic MCL1 gene product is regulated by a mitogen activated protein kinase-mediated pathway triggered through microtubule disruption and protein kinase C. Townsend, K.J., Trusty, J.L., Traupman, M.A., Eastman, A., Craig, R.W. Oncogene (1998) [Pubmed]
  22. BH3-ligand regulates access of MCL-1 to its E3 ligase. Warr, M.R., Acoca, S., Liu, Z., Germain, M., Watson, M., Blanchette, M., Wing, S.S., Shore, G.C. FEBS Lett. (2005) [Pubmed]
  23. 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, C.P., Hsu, S.Y., Hsueh, A.J. J. Biol. Chem. (2000) [Pubmed]
  24. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Leu, J.I., Dumont, P., Hafey, M., Murphy, M.E., George, D.L. Nat. Cell Biol. (2004) [Pubmed]
  25. Induction of BCL2 family member MCL1 as an early response to DNA damage. Zhan, Q., Bieszczad, C.K., Bae, I., Fornace, A.J., Craig, R.W. Oncogene (1997) [Pubmed]
  26. Gene expression analysis of 1,25(OH)2D3-dependent differentiation of HL-60 cells: a cDNA array study. Savli, H., Aalto, Y., Nagy, B., Knuutila, S., Pakkala, S. Br. J. Haematol. (2002) [Pubmed]
  27. Expression of ced-3 and ced-9 homologs in Alzheimer's disease cerebral cortex. Desjardins, P., Ledoux, S. Neurosci. Lett. (1998) [Pubmed]
  28. A collagenous protective coat enables Metarhizium anisopliae to evade insect immune responses. Wang, C., St Leger, R.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  29. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. Foran, J.M., Rohatiner, A.Z., Cunningham, D., Popescu, R.A., Solal-Celigny, P., Ghielmini, M., Coiffier, B., Johnson, P.W., Gisselbrecht, C., Reyes, F., Radford, J.A., Bessell, E.M., Souleau, B., Benzohra, A., Lister, T.A. J. Clin. Oncol. (2000) [Pubmed]
  30. Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Hogarth, L.A., Hall, A.G. Blood (1999) [Pubmed]
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