Human papillomavirus E7 requires the protease calpain to degrade the retinoblastoma protein.
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.
Darnell
Grant A
GA
Immunovirology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Schroder
Wayne A
WA
Antalis
Toni M
TM
Lambley
Eleanore
E
Major
Lee
L
Gardner
Joy
J
Birrell
Geoff
G
Cid-Arregui
Angel
A
Suhrbier
Andreas
A
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
D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D001616:beta-Galactosidase; D002154:Calpain