title: Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain.
abstract: Unlike other antiapoptotic Bcl-2 family members, Mcl-1 also mediates resistance to cancer therapy by uniquely inhibiting chemotherapy-induced senescence (CIS). In general, Bcl-2 family members regulate apoptosis at the level of the mitochondria through a common prosurvival binding groove. Through mutagenesis, we determined that Mcl-1 can inhibit CIS even in the absence of its apoptotically important mitochondrion-localizing domains. This finding prompted us to generate a series of Mcl-1 deletion mutants from both the N and C termini of the protein, including one that contained a deletion of all of the Bcl-2 homology domains, none of which impacted anti-CIS capabilities. Through subsequent structure-function analyses of Mcl-1, we identified a previously uncharacterized loop domain responsible for the anti-CIS activity of Mcl-1. The importance of the loop domain was confirmed in multiple tumor types, two in vivo models of senescence, and by demonstrating that a peptide mimetic of the loop domain can effectively inhibit the anti-CIS function of Mcl-1. The results from our studies appear to be highly translatable because we discerned an inverse relationship between the expression of Mcl-1 and of various senescence markers in cancerous human tissues. In summary, our findings regarding the unique structural properties of Mcl-1 provide new approaches for targeted cancer therapy.
authors.affiliation: From the Departments of Immunology and.
authors.forename: Abeba
authors.initials: A
authors.lastname: Demelash
authors.affiliation: From the Departments of Immunology and.
authors.forename: Lukas W
authors.initials: LW
authors.lastname: Pfannenstiel
authors.affiliation: From the Departments of Immunology and.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Tannenbaum
authors.affiliation: From the Departments of Immunology and.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Kalady
authors.affiliation: Stem Cell Biology and Regenerative Medicine, Lerner Research Institute.
authors.forename: Jennifer
authors.initials: J
authors.lastname: DeVecchio
authors.affiliation: From the Departments of Immunology and Institutes of Head and Neck, Dermatology, and Plastic Surgery, Taussig Cancer Center; and gastmab@ccf.org.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Gastman
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D004317:Doxorubicin
keywords: biomarker; cancer; cancer therapy; cell-penetrating peptide (CPP); chemoresistance; protein domain; senescence