Lunar Phase Influence on Global Temperatures
R24C is selectively impaired in its interaction with p16INK4a and p15INK4b and suggest that Arg24 is directly involved in binding to p16INK4a and p15INK4b. The cell cycle regulatory pathway that involves the retinoblastoma protein (Rb), cyclin D1, p161NK4a, and CDK4 has been implicated in tumorigenesis (21). In particular, p16INK4a can inhibit cell proliferation and oncogenic transformation of cultured cells (22). Inactivation of the gene encoding pl6INK4a is common in some tumor cell lines and
... primary tumors and is responsible for genetic predisposition to melanoma (23). Mutation of CDK4 at positions that disrupt its interaction with p16INK4a may constitute a mechanism to subvert this regulatory pathway in tumor cells. It seems plausible that, aside from its antigenicity, the expression of CDK4-R24C contributed to malignant transformation in melanoma SK29(AV). Antigens derived from oncogenic proteins are ideally suited as targets of tumor rejection responses because tumorigenesis is likely to depend on the continued expression of the antigen. Indeed, CTLs against viral oncoproteins have been demonstrated to elicit rejection response and protective immunity to virally induced murine tumors (24) . It remains to be proven that human tumor-specific antigens like CDK4-R24C can constitute targets for rejection response in vivo. However, it should be noted that patient SK29(AV) has been free of detectable disease since 1978 (7). 13. DNA was extracted from four allogeneic melanoma lines and from paraffin-embedded melanoma tumor samples of 24 patients as described (25). A 270-bp CDK4 genomic fragment was amplified with primers 5'-ATGGCTACCTCTCGATATGAGC-CAGTG (codons 1 to 9) and 5'-AGGCTGTCTTTT-CCCTTTACTCCCCA [binding to intron sequence (26)]. By using an exon-intron primer pair, contamination with cDNA was excluded. Amplified CDK4 fragments were purified and directly sequenced as shown in Fig. 2 . DNA sequences from 27 of 28 melanomas were identical to that of wild-type CDK4. One melanoma tumor carried both CGT nar-climate interactions.