A Novel Mcl1 Variant Inhibits Apoptosis Via Increased Bim Sequestration

Overview

Journal Oncotarget

Specialty Oncology

Date 2013 Jul 23

PMID 23872733

Citations 8

Authors

Judith Hagenbuchner

Ursula Kiechl-Kohlendorfer

Petra Obexer

Michael J Ausserlechner

Affiliations

Soon will be listed here.

Abstract

Members of the Bcl-2 protein family are frequently deregulated in tumors as they critically control cell death induction in mammalian cells. Alterations of these proteins may cause resistance to chemotherapy-induced cell death and immune responses. By serendipity we cloned a variant of the anti-apoptotic Bcl2-family member Myeloid cell leukemia-1 (Mcl1) from human neuroblastoma and leukemia cells. This Mcl1L variant lacks a 45 bp sequence that codes for 15 highly conserved amino acids ranging from Gly158 to Asp172. This region is part of the so called PEST-sequence of Mcl1L and contains two phosphorylation sites (Ser159 and Thr163) that regulate Mcl1L stability. A caspase 3/caspase 8 cleavage site at Asp157 which has been reported to be critical for death-receptor-induced apoptosis and for the conversion of Mcl1L into a pro-apoptotic protein is also missing in this novel variant. Importantly, Mcl1LdelGly158-Asp172 bound significantly more pro-apoptotic Bim compared to Mcl1L and showed increased anti-proliferative and anti-apoptotic activity compared to Mcl1L during death receptor-induced cell death. This suggests that this novel Mcl1L variant efficiently protects tumor cells against extrinsic death signalling and therefore may provide a survival advantage for highly aggressive tumors.

Citing Articles

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FOXO3-mediated chemo-protection in high-stage neuroblastoma depends on wild-type TP53 and SESN3.

Rupp M, Hagenbuchner J, Rass B, Fiegl H, Kiechl-Kohlendorfer U, Obexer P Oncogene. 2017; 36(44):6190-6203.

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