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Gene Review

Mcl1  -  myeloid cell leukemia sequence 1

Mus musculus

Synonyms: AW556805, Bcl-2-related protein EAT/mcl1, Induced myeloid leukemia cell differentiation protein Mcl-1 homolog, Mcl-1
 
 
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Disease relevance of Mcl1

  • Up-regulated expression of murine Mcl1/EAT, a bcl-2 related gene, in the early stage of differentiation of murine embryonal carcinoma cells and embryonic stem cells [1].
  • Furthermore, enforced Mcl-1 expression in a mouse lymphoma model conferred resistance [2].
  • Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription [3].
  • Increased expression of Mcl-1 is required for protection against serum starvation in phosphatase and tensin homologue on chromosome 10 null mouse embryonic fibroblasts, but repression of Bim is favored in human glioblastomas [4].
  • Thus, tumor hypoxia and ER stress may provide a physiological selective pressure for the expansion of the high-metastatic cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors [5].
 

High impact information on Mcl1

  • Of note, Mcl-1(-/-) blastocysts showed no evidence of increased apoptosis, but exhibited a delay in maturation beyond the precompaction stage [6].
  • Strikingly, Noxa bound only Mcl-1 and A1 [7].
  • Several BH3 peptides relieved the inhibition of Bax caused by the antiapoptotic Bcl-x(L) and/or Mcl-1 proteins, some displaying a specificity for either Bcl-x(L) or Mcl-1 [8].
  • Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this alpha-apoptotic gene product may play an important role in PC survival [9].
  • Upon exposure to pneumococci, macrophages initially upregulate Mcl-1 protein and maintain viability for up to 14 hours [10].
 

Chemical compound and disease context of Mcl1

 

Biological context of Mcl1

 

Anatomical context of Mcl1

  • The B cell lymphoma-2 (Bcl-2) homologs myeloid cell leukemia-1 (Mcl-1) and A1 are prosurvival factors that selectively bind a subset of proapoptotic Bcl homology (BH) 3-only proteins [15].
  • In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold [3].
  • Using laser capture microdissection followed by RT-PCR, we determined that Mcl-1 mRNA was expressed in granule cells, but not in Purkinje cells [16].
  • These data suggest that anti-apoptotic Mcl-1 may mediate IGF-I pro-survival actions on granule neurons during the development of cerebellar cortex [16].
  • Induced deletion of Mcl-1 in peripheral B- and T-cell populations resulted in their rapid loss [17].
 

Associations of Mcl1 with chemical compounds

 

Regulatory relationships of Mcl1

  • Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation [18].
  • Expression of Mcl-1 in cerebellar granule neurons is regulated by IGF-I in a developmentally specific fashion [16].
  • We explored effects of oridonin on antiapoptotic Bcl-2 family members and found that it down-regulated levels of Mcl-1 and BCL-x(L), but not Bcl-2 protein, in both MT-1 and RPMI8226 cells [21].
  • Furthermore, expression of ErbB1 alone or in combination with ErbB2 in NIH3T3 cells up-regulates Mcl-1 following EGF treatment [22].
 

Other interactions of Mcl1

 

Analytical, diagnostic and therapeutic context of Mcl1

  • Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity [3].
  • Semiquantitative and real-time RT-PCR revealed that Bcl-xL and Mcl-1 mRNAs are the dominant anti-apoptotic members and increase four- and twofold, respectively, with maturation [24].
  • Contrary to the results obtained by cDNA array, Northern blot analyses showed that the Mcl-1 mRNA abundance in the cerebella of IGF-I Tg mice at postnatal day 14 (P14) was five times more than that of wild-type (Wt) controls [16].
  • Further, by profiling gene expression using the same microarray platform, we identified within CNAs the relevant subset of candidate cancer genes displaying comparably altered expression, including Mcl1 (myeloid cell leukemia sequence 1), a highly expressed antiapoptotic gene residing within the chr 3 amplicon peak [25].
  • Apoptosis was detected within 4 hours of Mcl-1 antisense treatment by a variety of parameters including a novel live cell imaging technique allowing correlation of antisense treatment and apoptosis in individual cells [19].

References

  1. Up-regulated expression of murine Mcl1/EAT, a bcl-2 related gene, in the early stage of differentiation of murine embryonal carcinoma cells and embryonic stem cells. Okita, H., Umezawa, A., Suzuki, A., Hata, J. Biochim. Biophys. Acta (1998) [Pubmed]
  2. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. van Delft, M.F., Wei, A.H., Mason, K.D., Vandenberg, C.J., Chen, L., Czabotar, P.E., Willis, S.N., Scott, C.L., Day, C.L., Cory, S., Adams, J.M., Roberts, A.W., Huang, D.C. Cancer Cell (2006) [Pubmed]
  3. Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. Baskin-Bey, E.S., Huang, W., Ishimura, N., Isomoto, H., Bronk, S.F., Braley, K., Craig, R.W., Moore, D.D., Gores, G.J. Hepatology (2006) [Pubmed]
  4. Increased expression of Mcl-1 is required for protection against serum starvation in phosphatase and tensin homologue on chromosome 10 null mouse embryonic fibroblasts, but repression of Bim is favored in human glioblastomas. Austin, M., Cook, S.J. J. Biol. Chem. (2005) [Pubmed]
  5. Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors. Koshikawa, N., Maejima, C., Miyazaki, K., Nakagawara, A., Takenaga, K. Oncogene (2006) [Pubmed]
  6. Mcl-1 deficiency results in peri-implantation embryonic lethality. Rinkenberger, J.L., Horning, S., Klocke, B., Roth, K., Korsmeyer, S.J. Genes Dev. (2000) [Pubmed]
  7. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Chen, L., Willis, S.N., Wei, A., Smith, B.J., Fletcher, J.I., Hinds, M.G., Colman, P.M., Day, C.L., Adams, J.M., Huang, D.C. Mol. Cell (2005) [Pubmed]
  8. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Kuwana, T., Bouchier-Hayes, L., Chipuk, J.E., Bonzon, C., Sullivan, B.A., Green, D.R., Newmeyer, D.D. Mol. Cell (2005) [Pubmed]
  9. BCMA is essential for the survival of long-lived bone marrow plasma cells. O'Connor, B.P., Raman, V.S., Erickson, L.D., Cook, W.J., Weaver, L.K., Ahonen, C., Lin, L.L., Mantchev, G.T., Bram, R.J., Noelle, R.J. J. Exp. Med. (2004) [Pubmed]
  10. Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. Marriott, H.M., Bingle, C.D., Read, R.C., Braley, K.E., Kroemer, G., Hellewell, P.G., Craig, R.W., Whyte, M.K., Dockrell, D.H. J. Clin. Invest. (2005) [Pubmed]
  11. Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of mcl-1 antisense oligonucleotides with low-dose cyclophosphamide. Thallinger, C., Wolschek, M.F., Maierhofer, H., Skvara, H., Pehamberger, H., Monia, B.P., Jansen, B., Wacheck, V., Selzer, E. Clin. Cancer Res. (2004) [Pubmed]
  12. 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. MacCallum, D.E., Melville, J., Frame, S., Watt, K., Anderson, S., Gianella-Borradori, A., Lane, D.P., Green, S.R. Cancer Res. (2005) [Pubmed]
  13. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Ma, Y., Cress, W.D., Haura, E.B. Mol. Cancer Ther. (2003) [Pubmed]
  14. Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons. Mori, M., Burgess, D.L., Gefrides, L.A., Foreman, P.J., Opferman, J.T., Korsmeyer, S.J., Cavalheiro, E.A., Naffah-Mazzacoratti, M.G., Noebels, J.L. Cell Death Differ. (2004) [Pubmed]
  15. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. Day, C.L., Chen, L., Richardson, S.J., Harrison, P.J., Huang, D.C., Hinds, M.G. J. Biol. Chem. (2005) [Pubmed]
  16. Expression of Mcl-1 in cerebellar granule neurons is regulated by IGF-I in a developmentally specific fashion. Zhang, J., D'Ercole, A.J. Brain Res. Dev. Brain Res. (2004) [Pubmed]
  17. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Opferman, J.T., Letai, A., Beard, C., Sorcinelli, M.D., Ong, C.C., Korsmeyer, S.J. Nature (2003) [Pubmed]
  18. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Chen, S., Dai, Y., Harada, H., Dent, P., Grant, S. Cancer Res. (2007) [Pubmed]
  19. Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells. Moulding, D.A., Giles, R.V., Spiller, D.G., White, M.R., Tidd, D.M., Edwards, S.W. Blood (2000) [Pubmed]
  20. Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Michels, J., O'Neill, J.W., Dallman, C.L., Mouzakiti, A., Habens, F., Brimmell, M., Zhang, K.Y., Craig, R.W., Marcusson, E.G., Johnson, P.W., Packham, G. Oncogene (2004) [Pubmed]
  21. Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-kappa B signal pathways. Ikezoe, T., Yang, Y., Bandobashi, K., Saito, T., Takemoto, S., Machida, H., Togitani, K., Koeffler, H.P., Taguchi, H. Mol. Cancer Ther. (2005) [Pubmed]
  22. Increased expression of Mcl-1 is responsible for the blockage of TRAIL-induced apoptosis mediated by EGF/ErbB1 signaling pathway. Henson, E.S., Gibson, E.M., Villanueva, J., Bristow, N.A., Haney, N., Gibson, S.B. J. Cell. Biochem. (2003) [Pubmed]
  23. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. Meng, F., Yamagiwa, Y., Ueno, Y., Patel, T. J. Hepatol. (2006) [Pubmed]
  24. Bcl-2-related protein family gene expression during oligodendroglial differentiation. Itoh, T., Itoh, A., Pleasure, D. J. Neurochem. (2003) [Pubmed]
  25. Comparative genomic hybridization on mouse cDNA microarrays and its application to a murine lymphoma model. Sander, S., Bullinger, L., Karlsson, A., Giuriato, S., Hernandez-Boussard, T., Felsher, D.W., Pollack, J.R. Oncogene (2005) [Pubmed]
 
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