Tumor cell lines with a defective retinoblastoma gene are unableto transcribe the HLA class II genes in response to IFN- treatment,and reconstitution of functional Rb rescues IFN--induced classII gene expression. However, the molecular mechanism of Rb rescueof the class II genes is unknown. We have examined the effectof Rb expression on the activation of the promoter for HLA-DRA,the prototype class II gene. Oct-1, a POU domain transcriptionfactor, was identified as a repressor of HLA-DRA promoter activityin the Rb-defective cells. Rb expression led to phosphorylationof Oct-1, thus relieving its repressive effect. Oct-1 has alsobeen shown to repress interleukin 8 promoter activity. Consistentwith reduced levels of Oct-1 DNA binding activity in the Rb-transformedcell lines, interleukin 8 expression is higher in these celllines.