INTERFERENCE WITH THE EXPRESSION OF A NOVEL HUMAN POLYCOMB PROTEIN, HPC2, RESULTS IN CELLULAR-TRANSFORMATION AND APOPTOSIS

Polycomb (Pc) is involved in the stable and heritable repression of ho meotic gene activity during Drosophila development. Here, we report th e identification of a novel human Pc homolog, hPc2. This gene is more closely related to a Xenopus Pc homolog, XPc, than to a previously des cribed human Pc homolog, CBX2 (hPc1). However, the hPc2 and CBX2/hPc1 proteins colocalize in interphase nuclei of human U-2 OS osteosarcoma cells, suggesting that the proteins are part of a common protein compl ex, To study the functions of the novel human Pc homolog, we generated a mutant protein, Delta hPc2, which lacks an evolutionarily conserved C-terminal domain, This C-terminal domain is important for hPc2 funct ion, since the Delta hPc2 mutant protein which lacks the C-terminal do main is unable to repress gene activity. Expression of the Delta hPc2 protein, but not of the wild-type hPc2 protein, results in cellular tr ansformation of mammalian cell lines as judged by phenotypic changes, altered marker gene expression, and anchorage-independent growth. Spec ifically in Delta hPc2-transformed cells, the expression of the c-myc proto-oncogene is strongly enhanced and serum deprivation results in a poptosis, In contrast, overexpression of the wild-type hPc2 protein re sults in decreased c-myc expression. Our data suggest that hPc2 is a r epressor of proto-oncogene activity and that interference with hPc2 fu nction can lead to derepression of proto-oncogene transcription and su bsequently to cellular transformation.