Jab1/CSN5 induces the cytoplasmic localization and degradation of RUNX3

Abstract Runt‐related (RUNX) transcription factors play pivotal roles in neoplastic development and have tissue‐specific developmental roles in hematopoiesis ( RUNX1 ), osteogenesis ( RUNX2 ), as well as neurogenesis and thymopoiesis ( RUNX3 ). RUNX3 is a tumor suppressor in gastric carcinoma, and its expression is frequently inactivated by DNA methylation or its protein mislocalized in many cancer types, including gastric and breast cancer. Jun‐activation domain‐binding protein 1 (Jab1/CSN5), a component of the COP9 signalosome (CSN), is critical for nuclear export and the degradation of several tumor suppressor proteins, including p53, p27 Kip1 , and Smad4. Here, we find that Jab1 facilitates nuclear export of RUNX3 that is controlled by CSN‐associated kinases. RUNX3 sequestered in the cytoplasm is rapidly degraded through a proteasome‐mediated pathway. Our results identify a novel mechanism of regulating nuclear export and protein stability of RUNX3 by the CSN complex. J. Cell. Biochem. 107: 557–565, 2009. © 2009 Wiley‐Liss, Inc.