p53 is a phosphoprotein implicated in the control of the cell cycle and cell growth, and p53 is expressed in normal and immortalized human keratinocytes and epidermis. P53 bioactivity is regulated, in part, by phosphorylation status, nuclear
localization and complexation with cofactors or viral oncoproteins, including SV40 large T antigen and human papillomavirus(HPV) E6 transforming protein. I have investigated the expression and localization of p53 and the effects of non-cytotoxic
doses
of ultraviolet B(UVB) or ionizing (gamma) radiation on cell cycle arrest cycle arrest in normal or virally(HPV) immortalized human keratinocytes (HPK1A).
I etablished that doses of 10-15mJ/cm* UVB and 400 cGy gamma radiation induce reversible growth arrest in normal keratinocytes. Within 8-24 hours of expoure, G1/G2 phase accumulation and S phase depletion develop. Cell cycle-specific growth
arrest
was
pronounced at 8-24 hours as assessed by dual parameter measurement of bromodeoxyuridine incorporation and propidium iodide DNA histography. Cell cycle traverse and proliferation resumed 24-48 hours following irradiation of normal keratinocytes.
However,
the selectively immortalized keratinocyte cell line(HPK1A) demonstrated constitutive localization of nuclear, but virally complexed and inactivated p53. Exposure to similar doses of UVB or gamma radiation failed to significantly alter cell cycle
profiles and induce reversible cell growth arrest.
These studies demonstrate resistance of selected, virallly altered human keratinocyte to growth arrest following non-cytotoxic but mutagenic doses of radiation. The findings provide further evidence implicating altered p53 function in the
development
and propagation of genomic mutations which may lead to cellular transformation and subsequent carcinogenic events in epidermis.
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