Rb protein down-regulates the stress-activated signals through inhibiting c-Jun N-terminal kinase/stress-activated protein kinase

The Rb protein is the product of the retinoblastoma susceptibility gene and loss of Rb function is detected in many types of human cancers. Rb plays i mportant roles in the regulation of cell proliferation, differentiation, se nescence, and apoptotic cell death. Here we show that Rb can physically int eract with c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/S APK), thereby inhibiting intracellular signals mediated by JNK/SAPK. Both i n vitro binding and in vitro kinase studies suggest that a carboxyl-termina l domain of Rb containing amino acids 768-928 might be crucial for inhibiti ng JNK/SAPK. In comparison, Rb did not affect enzymatic activity of either extracellular signal-regulated kinase 1 or p38. Ectopically expressed Rb al so abrogated the apoptotic cell death induced by ultraviolet radiation or t he activation of MEKK1, an upstream kinase that can stimulate the JNK/SAPK cascade. JNK/ SAPK inhibition highlights a novel function of Rb, which may provide a new mechanism by which Rb regulates cell death. JNK/SAPK is a maj or protein kinase that can be stimulated in response to a variety of cellul ar stresses. Our results, therefore, suggest that Rb, by inhibiting JNK/SAP K, may act as a negative regulator in stress-activated intracellular signal ing cascades.