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SMAD4 suppresses AURKA-induced metastatic phenotypes via degradation of AURKA in a TGFß-independent manner.
Jia, Lina; Lee, Hun Seok; Wu, Chun Fu; Kundu, Juthika; Park, Sang Gyu; Kim, Ryong Nam; Wang, Li-Hui; Erkin, Özgür Cem; Choi, Jong-Sun; Chae, Seoung Wan; Yang, Ho Bin; Choi, Yoon-La; Shin, Young Kee.
Afiliación
  • Jia L; Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
  • Lee HS; Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
  • Wu CF; Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
  • Kundu J; College of Pharmacy, Keimyung University, Deagu, Korea.
  • Park SG; Department of Pharmacy, College of Pharmacy, Ajou University, Gyuggido, Korea.
  • Kim RN; Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea.
  • Wang LH; Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
  • Erkin ÖC; Department of Bioengineering, Faculty of Engineering, Adana Science and Technology, Adana, Turkey.
  • Choi JS; Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea.
  • Chae SW; Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Yang HB; Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
  • Choi YL; Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Shin YK; Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea. Institutes of Entrepreneurial BioConvergence, Seoul National University, Se
Mol Cancer Res ; 12(12): 1779-95, 2014 Dec.
Article en En | MEDLINE | ID: mdl-25061104
UNLABELLED: SMAD4 has been suggested to inhibit the activity of the WNT/ß-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/ß-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of ß-catenin/T-cell factor (TCF) complex by stabilizing ß-catenin through the inhibition of GSK-3ß. Here, SMAD4 modulated AURKA in a TGFß-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function, including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the ß-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of ß-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and ß-catenin was independent of TGFß signaling because blockage of TGFßR1 or restoration of TGFß signaling did not prevent suppression of AURKA and ß-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by downregulation of ß-catenin transcriptional activity via AURKA degradation in a TGFß-independent manner. IMPLICATIONS: SMAD4 interacts with AURKA and antagonizes its tumor-promoting potential, thus demonstrating a novel mechanism of tumor suppression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta / Proteína Smad4 / Beta Catenina / Aurora Quinasa A / Neoplasias Límite: Animals / Humans Idioma: En Revista: Mol Cancer Res Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2014 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta / Proteína Smad4 / Beta Catenina / Aurora Quinasa A / Neoplasias Límite: Animals / Humans Idioma: En Revista: Mol Cancer Res Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2014 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos