Mcl-1 regulation and its role in multiple myeloma.
Among the Bcl-2 family, myeloid cell leukemia-1 (Mcl-1) distinguishes itself from the other pro-survival proteins by its ability to oppose to a wide variety of pro-apoptotic stimuli, short half-life, and presence of polypeptide sequences enriched in proline (P), glutamic acid (E), serine (S) and threonine (T) domains (PEST). Moreover, Mcl-1 undergoes a complex transcriptional, post-transcriptional, and post-translational regulation process. This regulation modifies not only Mcl-1 expression, but also its function. Various extra-cellular stimuli, including cytokines, growth factors, 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and IFN, activate pathways which regulate Mcl-1 expression. Furthermore, Mcl-1 can be alternatively spliced into a long (Mcl-1) or a short (Mcl-1S) form. Mcl-1 opposes pro-apoptotic proteins and can be either cleaved or phosphorylated at a post-translational level. Mcl-1-spliced products, Mcl-1-cleaved products, or phosphorylated Mcl-1 have either a pro or an anti-apoptotic function, highlighting the complexity and pivotal role of Mcl-1 regulation. Here we discuss the regulation and function of Mcl-1 in the pathophysiology of multiple myeloma.
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
Steven
S
Le Gouill
Klaus
K
Podar
Jean-Luc
JL
Harousseau
Kenneth C
KC
Anderson
D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A