ABERRATIONS OF P16(INK4) AND RETINOBLASTOMA TUMOR-SUPPRESSOR GENES OCCUR IN DISTINCT SUB-SETS OF HUMAN CANCER CELL-LINES

The p16(Ink4)/MTSI/CDKN2 is a cell-cycle regulatory inhibitor of cycli n-dependent kinase 4 (cdk4), acid a candidate tumour suppressor whose gene on chromosome band 9p21 is frequently deleted or mutated in diver se types of cancer. Cdk4 in association with its D-type cyclin partner s, together with p16(Ink4), and the product of the retinoblastoma tumo ur-suppressor gene (pRB), appear to constitute a G(1)-phase-controllin g pathway which can become deregulated through oncogenic aberrations o f any of the components. In an attempt to elucidate the underlying mol ecular mechanisms, we have now surveyed expression of p16(Ink4) at the protein and the mRNA levels, in 21 human cell types expressing normal pRB, as compared with another series of 21 cell lines whose pRB is mu tant and/or inactivated through sequestration by DNA tumour virus onco proteins. In contrast to aberrant lack of p16 expression in the majori ty of RE-positive cell types, expression of apparently normal (as show n by electrophoretic mobility and/or the ability to form protein-prote in complexes with cdk4 in vivo) p16 was uniformly preserved in the can cer cell lines whose RE function was compromised. These data indicate that p16 operates upstream of pRB along the same pathway in G(1). The results are discussed in view of the nature of a selective growth adva ntage potentially gained by cells through de-regulation of this key ce ll-cycle control mechanism. (C) 1995 Wiley-Liss, Inc.