Mcl-1; the molecular regulation of protein function

Abstract 

Apoptosis, an essential and basic biological phenomenon, is regulated in a complex manner by a multitude of factors. Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family of apoptosis-regulating proteins, exemplifies a number of the mechanisms by which a protein’s contribution to cell fate may be modified. The N-terminus of Mcl-1 is unique amongst the Bcl-2 family, in that it is rich in experimentally confirmed and putative regulatory residues and motifs. These include sites for ubiquitination, cleavage and phosphorylation, which influence the protein’s stability, localisation, dimerization and function. Here we review what is known about the regulation of Mcl-1 expression and function, with particular focus on post-translational modifications and how phosphorylation interconnects the complex molecular control of Mcl-1 with cellular state.

Keywords: Apoptosis, Post-translational modification, Myeloid cell leukemia 1, Phosphorylation

Abbreviations: MCL-1, myeloid cell leukemia 1, BCL-2, B-cell lymphoma 2, BH, Bcl-2 homology, BCL-X_L, Bcl-2 like protein X, BID, BH3 interacting domain death agonist, PUMA, p53 upregulated modulator of apoptosis, BAX, Bcl-2-associated protein X, BAK, Bcl-2 homologous antagonist killer, BFL-1/A1, Bcl-2 related protein A1, PEST, proline/glutamic acid/serine/threonine, CDK-1, cyclin dependent kinase 1, PCNA, proliferating cell nuclear antigen, CHK-1, checkpoint 1 protein, IL, interleukin, GM-CSF, granulocyte–macrophage colony-stimulating factor, VEGF, vascular endothelial growth factor, STAT, signal transducers and activators of transcription, SRE, STAT response element, CRE, cAMP response element, NF-κB, nuclear factor kappa B, CREB, cAMP response element binding protein, HIF-1α, hypoxia-inducible factor 1α, Mir-29b, micro inhibiting RNA 29b, MULE, MCL-1 ubiquitin ligase, β-TrCP, beta transducin-containing protein, GrB, granzyme B, JNK, C-Jun N-terminal kinase, ERK, extracellular regulated protein kinase, Pin-1, peptidyl-prolyl cis-trans isomerase NIMA interacting protein 1, CHX, cycloheximide