Unraveling MCL-1 degradation

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

“…By contrast, bortezomib treatment for 24 or 48 h resulted in moderate up-regulation of the BH3 domain -only protein Bim and dramatic induction of the BH3 domain -only protein Bik. In addition, bortezomib caused marked up-regulation of Mcl-1L, an antiapoptotic protein whose expression levels in other cell types have been shown to be regulated by the proteasome (40). The expression levels of antiapoptotic Bcl-2 and Bcl-X L were not appreciably changed following bortezomib treatment, although a modest up-regulation of Bcl-X L was observed in 1483 cells.…”

Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

“…EGFR signaling might affect expression or activity of E3-ligases involved in Mcl-1 ubiquitination. 22 Also the activity of deubiquitinylases other than USP9X, which expression is not altered following Notch1 downregulation might be regulated through EGFR signaling. 25 Possible other mechanisms include phosphorylation and increased proteasomal degradation induced by PKC-y.…”

“…Notch1-mediated regulation of Mcl-1 is independent of several major signaling pathways To elucidate the mechanisms of Notch1-mediated post-translational regulation of Mcl-1 in glioblastomas, we examined the signaling events known to be involved in post-translational regulation of the Mcl-1 protein. 22 First, we tested the involvement of caspase-mediated cleavage 24 and deubiquitination by USP9X 25 in the Notch1-dependent regulation of Mcl-1, but none of these mechanisms were responsible for Mcl-1 protein reduction following Notch1-knockdown (Supplementary Figures S4A and B). Furthermore, we observed activation of GSK3b (glycogen synthase kinase 3b) and JNK (c-Jun N-terminal kinase) after Notch1 downregulation (Supplementary Figure S4C).…”

Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma

“…This is consistent with previous studies demonstrating Mcl-1 regulation by ubiquitination and proteasomal degradation. 35,36 CDK9 is known to associate with a protein complex, TAK/P-TEFb, which functions as an elongation factor for RNA polymerase II. CDK9 phosphorylates RNA polymerase II on Serine 2, thereby activating it.…”