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 activate...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-12, Vol.282 (52), p.37492-37500
Main Authors: Darnell, Grant A., Schroder, Wayne A., Antalis, Toni M., Lambley, Eleanore, Major, Lee, Gardner, Joy, Birrell, Geoff, Cid-Arregui, Angel, Suhrbier, Andreas
Format: Article
Language:English
Subjects:
Animals
beta-Galactosidase - metabolism
Binding Sites
Calpain - chemistry
Calpain - metabolism
Calpain - physiology
Cell Cycle
Cell Line
Cell Line, Tumor
Cellular Senescence
Fibroblasts - metabolism
Gene Expression Regulation, Neoplastic
Human papillomavirus
Humans
Mice
Models, Biological
Papillomaviridae - metabolism
Papillomavirus E7 Proteins - physiology
Protein Structure, Tertiary
Retinoblastoma Protein - chemistry
Retinoblastoma Protein - metabolism
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Summary: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 μ-calpain and promoted cleavage at Rb810, with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb1–810, was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Rb1–810. 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M706860200