Degradation of Mcl-1 by β-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization

Q Ding, X He, JM Hsu, W Xia, CT Chen… - … and cellular biology, 2007 - Taylor & Francis
Q Ding, X He, JM Hsu, W Xia, CT Chen, LY Li, DF Lee, JC Liu, Q Zhong, X Wang, MC Hung
Molecular and cellular biology, 2007Taylor & Francis
Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and
is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here,
we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and
we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3β
associates with and phosphorylates Mcl-1 at one consensus motif (155 S TDG159 S
LPS163 T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 …
Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3β associates with and phosphorylates Mcl-1 at one consensus motif (155STDG159SLPS163T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase β-TrCP, and β-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3β and then cannot be ubiquitinated by β-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3β and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by β-TrCP is an essential mechanism for GSK-3β-induced apoptosis and contributes to GSK-3β-mediated tumor suppression and chemosensitization.
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