A THYROID-HORMONE RECEPTOR COACTIVATOR NEGATIVELY REGULATED BY THE RETINOBLASTOMA PROTEIN

The retinoblastoma protein (Rb) plays a critical role in cell prolifer ation, differentiation, and development, To decipher the mechanism of Rb function at the molecular level, we have systematically characteriz ed a number of Rb-interacting proteins, among which is the clone C5 de scribed here, which encodes a protein of 1,978 amino acids with an est imated molecular mass of 230 kDa, The corresponding gene was assigned to chromosome 14q31, the same region where genetic alterations have be en associated with several abnormalities of thyroid hormone response, The protein uses two distinct regions to bind Rb and thyroid hormone r eceptor (TR), respectively, and thus mas named Trip230, Trip230 binds to Rb independently of thyroid hormone while it forms a complex with T R in a thyroid hormone-dependent manner, Ectopic expression of the pro tein Trip230 in cells, but not a mutant form that does not bind to TR, enhances specifically TR-dependent transcriptional activity, Coexpres sion of wild-type Rb, but not mutant Rb that fails to bind to Trip230, inhibits such activity, These results not only identify a coactivator molecule that modulates TR activity, but also uncover a role for Rb i n a pathway that responds to thyroid hormone.