Activation of telomerase and its association with G1-phase of the cell cycle during UVB-induced skin tumorigenesis in SKH-1 hairless mouse

Telomerase is a ribonucleoprotein enzyme that adds hexanucleotide repeats T TAGGG to the ends of chromosomes, Telomerase activation is known to play a crucial role in cell-immortalization and carcinogenesis. Telomerase is show n to have a correlation with cell cycle progression, which is controlled by the regulation of cyclins, cyclin dependent kinases (cdks) and cyclin depe ndent kinase inhibitors (cdkis), Abnormal expression of these regulatory mo lecules may cause alterations in cell cycle with uncontrolled cell growth, a universal feature of neoplasia, Skin cancer is the most prevalent form of cancer in humans and the solar UV radiation is its major cause. Here, we i nvestigated modulation in telomerase activity and protein expression of cel l cycle regulatory molecules during the development of UVB-induced tumors i n SKH-1 hairless mice, The mice were exposed to 180 mjoules/cm(2) UVB radia tion, thrice weekly for 24 weeks. The animals were sacrificed at 4 week int ervals and the studies were performed in epidermis, Telomerase activity was barely detectable in the epidermis of non-irradiated mouse. UVB exposure r esulted in a progressive increase in telomerase activity starting from the 4th week of exposure. The increased telomerase activity either persisted or further increased with the increased exposure, In papillomas and carcinoma s the enzyme activity was comparable and was 45-fold higher than in the epi dermis of control mice. Western blot analysis showed an upregulation in the protein expression of cyclin D1 and cyclin E and their regulatory subunits cdk4 and cdk2 during the course of UVB exposure and in papillomas and carc inomas. The protein expression of cdk6 and ckis viz, p16/Ink4A, p21/Waf1 an d p27/Kip1 did not show any significant change in WE exposed skin, but sign ificant upregulation was observed both in papillomas and carcinomas. The re sults suggest that telomerase activation may be involved in UVB-induced tum origenesis in mouse skin and that increased telomerase activity may be asso ciated with G1 phase of the cell cycle.