The initiation of UV-induced G(1) arrest in human cells is independent of the p53/p21/pRb pathway but can be attenuated through expression of the HPV E7 oncoprotein.
It is well established that the initiation of G(1) arrest in cultured cells exposed to ionizing radiation (IR) is fully dependent upon the p53/p21waf1/pRb signaling cascade. However, the extent to which this pathway regulates G(1) arrest following exposure to UV is less clear. Here we demonstrate that primary human fibroblasts from either skin or lung, in which p53 has been functionally inactivated through expression of the human papillomavirus E6 oncoprotein, each undergoes a prolonged G(1) arrest upon UV irradiation. This same phenomenon is also observed for UV-exposed human tumor cell strains that are genetically deficient for p53, p21waf1 and/or pRb. Furthermore, for the isogenic wild-type counterparts of these primary and tumor cell strains, the onset of UV-induced G(1) arrest precedes any increase in the ratio of hypo- to hyper-phosphorylated pRb and virtually the entire period of growth arrest occurs in the absence of p21waf1 induction. The above data on UV-treated cells are in contrast to the expected situation for IR, for which G(1) arrest is abolished in all deficient cell lines, and, in the wild-type counterparts, correlates precisely with p21waf1 induction and an increase in the ratio of hypo- to hyper-phosphorylated pRb. Remarkably, it was observed that both IR- and UV-induced G(1) arrest are significantly attenuated in primary fibroblasts expressing the human papillomavirus E7 oncoprotein, which functionally inactivates pRb in addition to many other cellular proteins. Our findings conclusively demonstrate that the p53/p21/pRb cascade is not essential for the initiation of G(1) arrest in UV-exposed human cells and, furthermore, indicate the involvement in this process of any among a number of human papillomavirus E7-interacting cellular proteins.
Loignon
Martin
M
Centre de Recherche Guy Bernier, Hôpital Maisonneuve-Rosemont, Faculty of Medecine, University of Montreal, 5415 Boulevard de l'Assomption, Montreal, Quebec HIT 2M4, Canada.
Drobetsky
Elliot A
EA
D002455:Cell Division / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D005434:Flow Cytometry; D016193:G1 Phase / Q000528:radiation effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000166:cytology / Q000528:radiation effects; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D012867:Skin / Q000166:cytology / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16