title: ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells.
abstract: The interferon-stimulated gene 15 (ISG15) pathway is highly elevated in breast cancer; however, very little is known about how the ISG15 pathway contributes to breast tumorigenesis. In the current study, using the gene disruption approach, we demonstrate that both ISG15 and UbcH8 (ISG15-specific conjugating enzyme) disrupt F-actin architecture and formation of focal adhesions in ZR-75-1 breast cancer cells. In addition, ISG15 and UbcH8 promote breast cancer cell migration. We also demonstrate that ISG15 inhibits ubiquitin/26S proteasome-mediated turnover of proteins implicated in tumor cell motility, invasion and metastasis. Together, our results suggest that the aberrant activation of the ISG15 pathway confers a motile phenotype to breast cancer cells by disrupting cell architecture and stabilizing proteins involved in cell motility, invasion and metastasis. Because the cellular architecture is conserved and the ISG15 pathway is constitutively activated in tumor cells of different lineages, it is reasonable to assume that our observations in breast cancer must hold true for many other tumors.
authors.affiliation: Department of Biochemistry and Molecular Biology, LSU Health Sciences Center-School of Medicine, 1901 Perdido Street, New Orleans, LA 70112, USA.
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Desai
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Reed
authors.forename: Julian
authors.initials: J
authors.lastname: Burks
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Wood
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Pullikuth
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Haas
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Jerome W
authors.initials: JW
authors.lastname: Breslin
authors.forename: Sally
authors.initials: S
authors.lastname: Meiners
authors.forename: Surendran
authors.initials: S
authors.lastname: Sankar
mesh_terms: D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007372:Interferons; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D016207:Cytokines; D034741:RNA, Small Interfering; D025801:Ubiquitin; D014452:Ubiquitins; C074034:ISG15 protein, human; D007372:Interferons; C471622:UBE2L6 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease