HUMAN NON-HODGKINS-LYMPHOMAS OVEREXPRESS A WILD-TYPE FORM OF P53 WHICH IS A FUNCTIONAL TRANSCRIPTIONAL ACTIVATOR OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21

A large fraction of non-Hodgkin's lymphomas (NHLs) accumulate a wild-t ype form of the p53 tumor suppressor protein at the nuclear level. In normal cells, p53 induction is associated with a temporary cell growth arrest at the G1-S boundary of the cell cycle. This activity of p53 a s a G1 checkpoint molecule is strictly dependent on its ability to ind uce the transcription of the inhibitor of the cyclin dependent kinase, p21. To verify the functionality of the wild-type p53 protein accumul ated in NHL cells, 70 cases were comparatively analyzed for p53 and p2 1 expression and status of the respective genes. Overexpression of the wt p53 protein was associated with the accumulation of p21, indicatin g that p53 is functional with respect to p21 induction in these tumors . The coaccumulation of p53 with Ki-67 antigen indicates that wt p53-p ositive cells and p21-positive cells, as well, are actively proliferat ive elements, supporting the notion that p53-induced, p21-mediated gro wth arrest is somehow overridden in NHL cells. No p21 mutation or part icular allele variant was shown to correlate with p21 protein accumula tion, thus excluding a role for p21 structural abnormalities. Taken to gether, our data suggest the existence in NHL of a peculiar mechanism of functional inactivation of the p53 G1 checkpoint pathway occurring downstream of the CDK inhibitor p21. (C) 1997 by The American Society of Hematology.