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Src Kinase Phosphorylates RUNX3 at Tyrosine Residues and Localizes the Protein in the Cytoplasm
Goh, Yun-Mi,Cinghu, Senthilkumar,Hong, Eileen Tan Hwee,Lee, You-Soub,Kim, Jang-Hyun,Jang, Ju-Won,Li, Ying-Hui,Chi, Xin-Zi,Lee, Kyeong-Sook,Wee, Heejun,Ito, Yoshiaki,Oh, Byung-Chul,Bae, Suk-Chul American Society for Biochemistry and Molecular Bi 2010 The Journal of biological chemistry Vol.285 No.13
<P>RUNX3 is a transcription factor that functions as a tumor suppressor. In some cancers, <I>RUNX3</I> expression is down-regulated, usually due to promoter hypermethylation. Recently, it was found that RUNX3 can also be inactivated by the mislocalization of the protein in the cytoplasm. The molecular mechanisms controlling this mislocalization are poorly understood. In this study, we found that the overexpression of Src results in the tyrosine phosphorylation and cytoplasmic localization of RUNX3. We also found that the tyrosine residues of endogenous RUNX3 are phosphorylated and that the protein is localized in the cytoplasm in Src-activated cancer cell lines. We further showed that the knockdown of <I>Src</I> by small interfering RNA, or the inhibition of Src kinase activity by a chemical inhibitor, causes the re-localization of RUNX3 to the nucleus. Collectively, our results demonstrate that the tyrosine phosphorylation of RUNX3 by activated Src is associated with the cytoplasmic localization of RUNX3 in gastric and breast cancers.</P>
Jab1/CSN5 induces the cytoplasmic localization and degradation of RUNX3
Kim, Jang-Hyun,Choi, Joong-Kook,Cinghu, Senthilkumar,Jang, Ju-Won,Lee, You-Soub,Li, Ying-Hui,Goh, Yun-Mi,Chi, Xin-Zi,Lee, Kyeong-Sook,Wee, Heejun,Bae, Suk-Chul Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of cellular biochemistry Vol.107 No.3
<P>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<SUP>Kip1</SUP>, 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.</P>
Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer
Lee, K-S,Lee, Y-S,Lee, J-M,Ito, K,Cinghu, S,Kim, J-H,Jang, J-W,Li, Y-H,Goh, Y-M,Chi, X-Z,Wee, H,Lee, H-W,Hosoya, A,Chung, J-H,Jang, J-J,Kundu, J K,Surh, Y-J,Kim, W-J,Ito, Y,Jung, H-S,Bae, S-C Macmillan Publishers Limited 2010 Oncogene Vol.29 No.23
Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3−/− mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3−/− bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3−/− epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/− mice (∼18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/− mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.