title: Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor.
abstract: Human papillomavirus type 16 (HPV16) and other high-risk HPVs are etiologically linked to the development of cervical carcinomas and contribute to a number of other tumors of the anogenital tract, as well as oral cancers. The high-risk HPV E6 and E7 oncoproteins are consistently expressed in cervical cancer cells and are necessary for the induction and maintenance of the transformed phenotype. An important aspect of HPV16 E7's oncogenic activities is destabilization of the retinoblastoma tumor suppressor (pRB) through a ubiquitin/proteasome-dependent mechanism, although the exact molecular mechanism is unknown. Here, we report that HPV16 E7 is associated with an enzymatically active cullin 2 ubiquitin ligase complex and that the HPV16 E7/pRB complex contains cullin 2. Depletion of cullin 2 by RNA interference causes increased steady-state levels and stability of pRB in HPV16 E7-expressing cells, and ectopic expression of HPV16 E7 and the cullin 2 complex leads to pRB ubiquitination in vivo. Hence, we propose that the HPV16 E7-associated cullin 2 ubiquitin ligase complex contributes to aberrant degradation of the pRB tumor suppressor in HPV16 E7-expressing cells.
authors.affiliation: The Channing Laboratory 861, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: KyungWon
authors.initials: K
authors.lastname: Huh
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Je-Yoel
authors.initials: JY
authors.lastname: Cho
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.forename: Karl
authors.initials: K
authors.lastname: Munger
mesh_terms: D002460:Cell Line; D002472:Cell Transformation, Viral / Q000502:physiology*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology
chemical_list: D044842:Cullin Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D025801:Ubiquitin; C059731:oncogene protein E7, Human papillomavirus type 16; D046988:Proteasome Endopeptidase Complex