title: Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility.
abstract: Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27(KIP1) as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27(KIP1). We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27(KIP1) during G1 phase of the cell cycle. p27(KIP1) lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27(KIP1), whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27(KIP1). In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27(KIP1) were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27(KIP1) to influence cervical cancer pathogenesis.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook Medicine, Stony Brook, New York. Department of Pathology, Stony Brook Medicine, Stony Brook, New York. Department of Biology, Research Group Genetic Toxicology and Cytogenetics, Department of Natural Sciences and Education, Universidad del Cauca, Popayán, Cauca, Colombia.
authors.forename: Luisa F
authors.initials: LF
authors.lastname: Escobar-Hoyos
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shah
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York. Department of Pathology, School of Medicine, National University of Colombia, Bogotá, Cundinamarca, Colombia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Roa-Peña
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Vanner
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Najafian
authors.affiliation: Molecular and Cellular Biology, Stony Brook Medicine, Stony Brook, New York.
authors.forename: Anna
authors.initials: A
authors.lastname: Banach
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
authors.forename: Erik
authors.initials: E
authors.lastname: Nielsen
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
authors.forename: Ramsey
authors.initials: R
authors.lastname: Al-Khalil
authors.affiliation: Department of Pathology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts.
authors.forename: Ali
authors.initials: A
authors.lastname: Akalin
authors.affiliation: Department of Pharmacological Sciences, Stony Brook Medicine, Stony Brook, New York.
authors.forename: David
authors.initials: D
authors.lastname: Talmage
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, New York. kenneth.shroyer@stonybrookmedicine.edu.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Shroyer
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D053537:Keratin-17 / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011485:Protein Binding; D059748:Proteolysis; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: C436291:CDKN1B protein, human; D053537:Keratin-17; D050760:Cyclin-Dependent Kinase Inhibitor p27