title: Inhibiting mitochondrial-dependent proteolysis of Mcl-1 promotes resistance to DNA damage.
abstract: Elimination of myeloid leukemia cell 1 (Mcl-1) is an early event in the onset of cell death following DNA damage and, in many settings, plays a critical role in dictating the success of chemotherapeutic agents. Following DNA damage, Mcl-1 is rapidly and efficiently targeted to the 26S proteasome through the action of E3 ubiquitin ligases. Tumors having acquired lesions that lead to stabilization of Mcl-1 are highly aggressive and have a poorer prognosis. Herein, we further characterize an additional mechanism of Mcl-1 proteolysis that is proteasome-independent but mitochondrial-dependent. A mitochondrial targeting signal located in the N terminus of Mcl-1 is essential for targeting Mcl-1 to this alternative degradative avenue. We demonstrate that the Akt/mTORC1 survival pathway protects Mcl-1 from mitochondrial-dependent proteolysis. Disrupting Mcl-1 inner mitochondrial targeting improves the pro-survival capacity of Mcl-1 both ex vivo and in vivo in the well-characterized mouse Eμ-Myc lymphoma model. Our data uncover an important relationship between the mitochondria and the Mcl-1 N terminus in dictating cell fate following DNA damage.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mills
authors.forename: Abba
authors.initials: A
authors.lastname: Malina
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004195:Disease Models, Animal; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D016296:Mutagenesis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex