A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration
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Judith Hagenbuchner1,3, Ursula Kiechl-Kohlendorfer1, Petra Obexer1,3, Michael J. Ausserlechner2,3
1 Department of Pediatrics II, Medical University Innsbruck, Austria
2 Department of Pediatrics I, Medical University Innsbruck, Austria
3 Tyrolean Cancer Research Institute, Innsbruck, Austria
Petra Obexer, email:
Michael Ausserlechner, email:
Keywords: Mcl1L, apoptosis, BCL2 proteins, mRNA variant
Received: July 1, 2013 Accepted: July 13, 2013 Published: July 15, 2013
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.
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