Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts.
The HPV16 E7 oncoprotein neutralizes several cell cycle checkpoints, favouring the entry of quiescent cells into S phase. This activity is mediated in part by association of E7 with the pocket proteins and consequent activation of E2F transcription factors. In addition, HPV16 E7 protein is able to promote apoptosis. In this study we demonstrate that the ability to induce apoptosis is a common property of E7s belonging to both benign and malignant HPV types. The E7-induced apoptosis is mediated by inactivation of pRb, whilst neutralization of the other two pRB-related proteins, p107 and 130, is not sufficient to trigger apoptosis. Moreover, we show that certain point mutations in the conserved region 1 (CR1) of HPV16 E7 abolish the induction of apoptosis without altering the ability to stimulate S phase. Thus, these two E7-mediated cellular events, apoptosis and S phase entry, can be separated in immortalized rodent fibroblasts. Our findings demonstrate that the E7-mediated pRb destabilization is not required for its ability to drive quiescent cells into S phase and to induce apoptosis. Finally, expression of E7 proteins in NIH3T3, which lack a functional p19ARF, does not lead to p53 accumulation, indicating that the E7 impacts upon additional cellular pathways to promote apoptosis.
Alunni-Fabbroni
M
M
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Littlewood
T
T
Deleu
L
L
Caldeira
S
S
Giarrè
M
M
Dell' Orco
M
M
Tommasino
M
M
D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002461:Cell Line, Transformed; D017124:Conserved Sequence; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016196:S Phase / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010750:Phosphoproteins; D011506:Proteins; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D004247:DNA