Papillomavirus E7 protein binding to the retinoblastoma protein is not required for viral induction of warts.
Human papillomaviruses (HPVs) are the etiologic agents responsible for benign epithelial proliferative disorders including genital warts and are a contributory factor in the pathogenesis of cervical cancer. HPVs demonstrate strict species and cell-type specificity, which is manifested by the inability of these viruses to induce disease in any species other than humans. The natural history of HPV infection in humans is closely mimicked by cottontail rabbit papillomavirus (CRPV) infection in domestic laboratory rabbits. The CRPV E7 gene is known to play an essential role in virus-mediated induction of papillomas. We now show by mutational analysis that the CRPV E7 protein's biochemical and biological properties, including binding to the retinoblastoma suppressor protein (pRB), transcription factor E2F transactivation of the adenovirus E2 promoter, disruption of pRB-E2F complexes, and cellular transformation as measured by growth in soft agar, mimic those of the HPV E7 protein. Intradermal injection of CRPV DNA lacking E7 gene sequences critical for the binding of the CRPV E7 protein to pRB induced papillomas in rabbits. These studies indicate that E7 protein binding to pRB is not required in the molecular pathogenesis of virally induced warts and suggest that other properties intrinsic to the E7 protein are necessary for papilloma formation.
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486.
D
D
Defeo-Jones
G A
GA
Vuocolo
K M
KM
Haskell
M G
MG
Hanobik
D M
DM
Kiefer
E M
EM
McAvoy
M
M
Ivey-Hoyle
J L
JL
Brandsma
A
A
Oliff
R E
RE
Jones
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002472:Cell Transformation, Viral; D012777:Cottontail rabbit papillomavirus / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005814:Genes, Viral / Q000235:genetics*; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011817:Rabbits; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D017386:Sequence Homology, Amino Acid; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014860:Warts / Q000209:etiology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; C079183:E7 protein, cottontail rabbit papillomavirus; D009856:Oncogene Proteins, Viral; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; C075621:oncogene protein E7, Bovine papillomavirus type 1