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Review
. 2013 Apr;14(4):328-36.
doi: 10.1038/embor.2013.20. Epub 2013 Mar 12.

Programming cancer cells for high expression levels of Mcl1

Franziska Ertel  1 , Mai Nguyen, Anne Roulston, Gordon C Shore
Affiliations
Review

Programming cancer cells for high expression levels of Mcl1

Franziska Ertel et al. EMBO Rep. 2013 Apr.

Abstract

The Bcl2 pro-survival protein family has long been recognized for its important contributions to cancer. At elevated levels relative to pro-apoptotic effector members, the survival proteins prevent cancer cells from initiating apoptosis in the face of many intrinsic tumour-suppressing pathways and extrinsic therapeutic treatments aimed at controlling tumorigenesis. Recent studies, including genome-wide analyses, have begun to focus attention on a particularly enigmatic member of the family-myeloid cell leukaemia 1 (Mcl1). For reasons that are not clear, Mcl1 in cancer cells is turned over rapidly, eliminated primarily through the ubiquitin-proteasome pathway. Moreover, the mechanistic aspects of this constitutive membrane-associated protein have not been fully elucidated. As the pro-cancer activity of Mcl1 requires elevated expression levels of the protein, the cancer genome adapts to ensure either high levels of synthesis or evasion of degradation, or both. Here, we focus on the complex strategies at play and their therapeutic implications.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
A model for Mcl1 regulation of Bak-dependent MOMP. As described in the text, Mcl1 and its binding partner Bak seem to have similarities to Bcl-XL and its binding partner Bax, with the exception that Mcl1 and Bak are constitutively anchored to the outer mitochondrial membrane (OMM) by their respective transmembrane segments. Hybrid models involving Mcl1/Bax and Bcl-XL/Bak are also relevant, as these interactions also exist. As in the Bcl-XL model, antagonism of Mcl1 by a sensitizing BH3-only protein (for example, Noxa) or by a chemical mimetic (such as, obatoclax or sabutoclax) can reinstate Bak-driven MOMP. As in the Bcl-XL model, the latter is probably seeded by Bak oligomers (pore progenitor) but requires additional membrane-dependent events to construct pores capable of releasing the protein content of the mitochondrial intermembrane space, including apoptotic regulators such as cytochrome c and Smac. Bak, Bcl2 antagonist killer; Bcl-XL, Bcl2-like protein XL; BH3, Bcl2 homology domain 3; COO−, carboxyl; Mcl1, myeloid cell leukaemia 1; MOMP, mitochondrial outer membrane permeabilization; Smac, second mitochondrial activator of caspase.
Figure 2
Figure 2
The Bcl2 family rheostat. There is substantial evidence for functional redundancy between pro-survival members, especially Bcl2, Mcl1 and Bcl-XL (upper rheostat). In this case, reduction of any one member could adjust the pro-survival rheostat below a crucial threshold, resulting in cell death in the face of cell stress signals. Alternatively, there might be situations in which unique pathways are regulated by the individual pro-survival members (lower rheostats). Although the Bcl2 family is most closely associated with apoptosis, there are or might be many other cellular responses or fates that are controlled by these proteins. Of particular relevance to Mcl1, changes to many cellular pathways can result in changes in the levels of Bcl2 family proteins, thereby regulating cell fate in the face of stress stimuli. Bak, Bcl2 antagonist killer; Bax, Bcl2-associated protein; Bcl2, B-cell lymphoma 2; Bcl-XL, Bcl2-like protein XL; Bim, Bcl2-like 11; Mcl1, myeloid cell leukaemia 1; Puma, p53 upregulated modulator of apoptosis; ROS, reactive oxygen species; tBid, truncated BH3-interacting domain death agonist.
Figure 3
Figure 3
The amino-terminal regulatory domain of Mcl1. As described in the text, this long (approximately 170 aa), flexible region is unique to Mcl1 among pro-survival Bcl2 proteins and is replete with regulatory sites. In addition to descriptions in the text, discussions about specific sites can be found in reference [5] and below. With the exception of L33 (mouse), amino acid number refers to the human sequence. Ser 64 can be phosphorylated by Cdk1 and Cdk2, and by Jnk1, which does not affect the protein half-life but leads to an enhanced survival function [96]. Erk1 phosphorylates Thr 92 and Thr1 63, which stabilizes Mcl1 through protein association with Pin [97]. Ser 121 in conjunction with Thr 163 is phosphorylated by Jnk, resulting in enhanced stability in one study [98] and unchanged stability but less potency at inhibiting apoptosis in a different study [99]. Ser 155 phosphorylation by Gsk3 decreases Mcl1 expression [69]. Ser 159 phosphorylation leads to Mcl1 destabilization and inhibits interaction with Bim [74], whereas phosphorylation of Thr 163 by Erk increases the half-life of Mcl1 [100]. Bcl2, B-cell lymphoma 2; Bim, Bcl2-like 11; Cdk1/2, cyclin-dependent kinase 1/2; Erk1, extracellular regulated protein kinase 1; Gsk3, glycogen synthase kinase 3; Jnk1, c-jun N-terminal kinase 1; Mcl1, myeloid cell leukaemia 1; PEST, proline/glutamic acid/serine/threonines; Pin, peptidyl-prolyl cis-trans isomerase NIMA interacting protein.
None
Gordon C Shore, Mai Nguyen, Franziska Ertel & Anne Roulston
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