C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis
| Autor: | Chhaya Das, Mark A. Brown, Melissa A. Edwards, Li Zhu, June V. Harriss, Haley O. Tucker, Kenneth W. Foreman, Salam Shaaban |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Carcinogenesis
Amino Acid Motifs Molecular Sequence Data Transfection Protein Structure Secondary Histones Mice HSP90 Animals Humans Amino Acid Sequence HSP90 Heat-Shock Proteins Cell Proliferation Genetics SMYD3 biology histone modifications C-terminus Methylation Histone-Lysine N-Methyltransferase Hsp90 Molecular biology Chromatin Protein Structure Tertiary lysine methylation Mice Inbred C57BL Tetratricopeptide tumorigenesis Histone Oncology Histone methyltransferase Chaperone (protein) biology.protein Mutagenesis Site-Directed NIH 3T3 Cells Protein Processing Post-Translational Sequence Alignment Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Mark A. Brown 1, * , Kenneth Foreman 2, * , June Harriss 3 , Chhaya Das 3 , Li Zhu 3 , Melissa Edwards 1, 3 , Salam Shaaban 4 , Haley Tucker 3 1 Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA 2 Coferon Inc., Stony Brook, NY 11791, USA 3 University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA 4 Abbvie, Worcester, MA 01605, USA * These authors have contributed equally to this work Correspondence to: Haley Tucker, e-mail: haleytucker@austin.utexas.edu Keywords: HSP90, SMYD3, tumorigenesis, lysine methylation, histone modifications Received: August 08, 2014 Accepted: December 16, 2014 Published: March 02, 2015 ABSTRACT The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been independently implicated as proto-oncogenes in several human malignancies. We show that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 C-terminal domain (CTD) mediates physical interaction with HSP90. We further demonstrate that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure is required for HSP90-enhanced enzyme activity. Loss of SMYD3-HSP90 interaction leads to SMYD3 mislocalization within the nucleus, thereby losing its chromatin association. This results in reduction of SMYD3-mediated cell proliferation and, potentially, impairment of SMYD3’s oncogenic activity. These results suggest a novel approach for blocking HSP90-driven malignancy in SMYD3-overexpressing cells with a reduced toxicity profile over current HSP90 inhibitors. |
| Databáze: | OpenAIRE |
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