title: Human papillomavirus E7 requires the protease calpain to degrade the retinoblastoma protein.
abstract: Cervical cancers transformed by high risk human papilloma virus (HPV) express the E7 oncoprotein, which accelerates the degradation of the retinoblastoma protein (Rb). Here we show that the E7-mediated degradation of Rb requires the calcium-activated cysteine protease, calpain. E7 bound and activated mu-calpain and promoted cleavage at Rb(810), with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb(1-810), was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Rb(1-810). Calpain inhibitors reduced the viability of HPV-transformed cells and synergized with cisplatin. Calpain, thus, emerges as a central player in E7-mediated degradation of Rb and represents a potential new drug target for the treatment of HPV-associated lesions.
authors.affiliation: Immunovirology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Darnell
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Schroder
authors.forename: Toni M
authors.initials: TM
authors.lastname: Antalis
authors.forename: Eleanore
authors.initials: E
authors.lastname: Lambley
authors.forename: Lee
authors.initials: L
authors.lastname: Major
authors.forename: Joy
authors.initials: J
authors.lastname: Gardner
authors.forename: Geoff
authors.initials: G
authors.lastname: Birrell
authors.forename: Angel
authors.initials: A
authors.lastname: Cid-Arregui
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
mesh_terms: D000818:Animals; D001665:Binding Sites; D002154:Calpain / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D027383:Papillomaviridae / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000502:physiology*; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D001616:beta-Galactosidase; D002154:Calpain