Our research is focused on the structure-function relationship of recently discovered tumor supressors p16 and p17. A number of studies show that mutations or deletions in the tumor suppressors correlate with the occurrence of familial melanoma, non-small cell lung adenocarcinoma, pancreatic adenocarcinoma, glioma, leukemia and other kinds of cancer. This tumor suppression activity is directly related with binding to cell cycle kinases, cdk4 and cdk6. This binding causes complete inhibition of the kinase activity of the cdk4-cyclin D complex or cdk6-cyclin D complex toward the retinoblastoma gene product (pRb). Since cdk4 and cdk6 play the most prominent roles in the regulation of G1-S transition in the cell cycle, p16 is one of the key cell-cycle regulators. We have successfully cloned and overexpressed p16 in E. coli. The preliminary NMR studies on p16 show it exhibits well dispersed spectral features. We propose to obtain total NMR assignments and determine solution structures of p16 and p15 by NMR in combination with 13C/15N isotopic labeling. The relatively small size (14-16 kDa) makes these suppressors ideal for detailed structural studies by NMR.
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