title: A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration.
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.
authors.affiliation: Department of Pediatrics II, Medical University Innsbruck, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Hagenbuchner
authors.forename: Ursula
authors.initials: U
authors.lastname: Kiechl-Kohlendorfer
authors.forename: Petra
authors.initials: P
authors.lastname: Obexer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ausserlechner
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger