EVIDENCE FOR RETINOBLASTOMA PROTEIN (RB) DEPENDENT AND INDEPENDENT IFN-GAMMA RESPONSES - RB COORDINATELY RESCUES IFN-GAMMA INDUCTION OF MHCCLASS-II GENE-TRANSCRIPTION IN NONINDUCIBLE BREAST-CARCINOMA CELLS

The class II major histocompatibility (MHC) genes encode cell surface heterodimers that present processed antigen to CD4 positive T-cells. T he class II genes are expressed constitutively on B-cells and can be i nduced by IFN-gamma on a variety of other cell types. Because the clas s II genes are aberrantly expressed on many mesenchymal tumors, which are frequently defective for the retinoblastoMa tumor suppressor prote in (RB), we investigated the role of RB in the regulation of HLA-DR an d -DP. The RB defective breast carcinomas cell line, MDA-468-S4 (S4), as well as S4 subclones reconstituted with RB coding sequences under t he control of a zinc inducible promoter, were treated with IFN-gamma a nd examined for DR and DP expression. Surface DR is not inducible in S 4 cells, but inducibility is rescued by RB. DP is only slightly induci ble in S4, but inducible to a much higher level in the RB positive sub clones of S4. IFN-gamma induction of DR and DP mRNAs are corresponding ly dependent on RB. IFN-gamma receptors are present on S4 cells, and t he guanylate binding protein and ICAM-1 genes respond to IFN-gamma, ru ling out the possibility that all IFN-gamma signal transduction pathwa ys are defective in S4 cells. These data indicate RB regulates the coo rdinate response of class II genes to IFN-gamma. Possible roles for RB in this process are discussed, as well as the role of the class II-no ninducible phenotype in tumor rejection.