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C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis
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 int...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414169/ https://www.ncbi.nlm.nih.gov/pubmed/25738358 |
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author | Brown, Mark A. Foreman, Kenneth Harriss, June Das, Chhaya Zhu, Li Edwards, Melissa Shaaban, Salam Tucker, Haley |
author_facet | Brown, Mark A. Foreman, Kenneth Harriss, June Das, Chhaya Zhu, Li Edwards, Melissa Shaaban, Salam Tucker, Haley |
author_sort | Brown, Mark A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4414169 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44141692015-05-08 C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis Brown, Mark A. Foreman, Kenneth Harriss, June Das, Chhaya Zhu, Li Edwards, Melissa Shaaban, Salam Tucker, Haley Oncotarget Research Paper 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. Impact Journals LLC 2015-02-12 /pmc/articles/PMC4414169/ /pubmed/25738358 Text en Copyright: © 2015 Brown et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Brown, Mark A. Foreman, Kenneth Harriss, June Das, Chhaya Zhu, Li Edwards, Melissa Shaaban, Salam Tucker, Haley C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis |
title | C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis |
title_full | C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis |
title_fullStr | C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis |
title_full_unstemmed | C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis |
title_short | C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis |
title_sort | c-terminal domain of smyd3 serves as a unique hsp90-regulated motif in oncogenesis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414169/ https://www.ncbi.nlm.nih.gov/pubmed/25738358 |
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