gamma-irradiation deregulates cell cycle control and apoptosis in nevoid basal cell carcinoma syndrome-derived cells

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant d isorder characterized by nevi, palmer and plantar pits, fair calcification, vertebrate anomalies and basal cell carcinomas. It is well known in NBCCS that gamma-irradiation to the skin induces basal cell carcinomas or causes an enlargement of the tumor size, although the details of the mechanism rem ain unknown, We have established lymphoblastoid cell lines from three NBCCS patients, and we present here the first evidence of abnormal cell cycle an d apoptosis regulations. A novel mutation (single nucleotide deletion) in t he coding region of the human patched gene, PTCH, was identified in two sib ling patients, but no apparent abnormalities were detected in the gene of t he remaining patient. Nevertheless, the three established cell lines showed similar features in the following analyses. Flow cytometric analyses revea led that the NBCCS-derived cells were accumulated in the G(2M) phase after gamma-irradiation, whereas normal cells showed cell cycle arrest both in th e G(0)G(1) and G(2)M phases. The fraction of apoptotic cells after gamma-ir radiation was smaller in the NBCCS cells, The level of p27 expression marke dly decreased after gamma-irradiation in the NBCCS cells, although the effe cts of the irradiation on the expression profiles for p53, p21 and Rb did n ot differ in normal and NBCCS cells. These findings may provide a clue to t he molecular mechanisms of tumorigenesis in NBCCS.