Cargando…
ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65
The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330387/ https://www.ncbi.nlm.nih.gov/pubmed/25609694 http://dx.doi.org/10.1093/nar/gkv026 |
_version_ | 1782357578542481408 |
---|---|
author | Kim, Min-Young Koh, Dong-In Choi, Won-Il Jeon, Bu-Nam Jeong, Deok-yoon Kim, Kyung-Sup Kim, Kunhong Kim, Se-Hoon Hur, Man-Wook |
author_facet | Kim, Min-Young Koh, Dong-In Choi, Won-Il Jeon, Bu-Nam Jeong, Deok-yoon Kim, Kyung-Sup Kim, Kunhong Kim, Se-Hoon Hur, Man-Wook |
author_sort | Kim, Min-Young |
collection | PubMed |
description | The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, −31 to −21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression. |
format | Online Article Text |
id | pubmed-4330387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-43303872015-03-18 ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 Kim, Min-Young Koh, Dong-In Choi, Won-Il Jeon, Bu-Nam Jeong, Deok-yoon Kim, Kyung-Sup Kim, Kunhong Kim, Se-Hoon Hur, Man-Wook Nucleic Acids Res Gene regulation, Chromatin and Epigenetics The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, −31 to −21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression. Oxford University Press 2015-02-18 2015-01-21 /pmc/articles/PMC4330387/ /pubmed/25609694 http://dx.doi.org/10.1093/nar/gkv026 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Gene regulation, Chromatin and Epigenetics Kim, Min-Young Koh, Dong-In Choi, Won-Il Jeon, Bu-Nam Jeong, Deok-yoon Kim, Kyung-Sup Kim, Kunhong Kim, Se-Hoon Hur, Man-Wook ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 |
title | ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 |
title_full | ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 |
title_fullStr | ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 |
title_full_unstemmed | ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 |
title_short | ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 |
title_sort | zbtb2 increases pdk4 expression by transcriptional repression of rela/p65 |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330387/ https://www.ncbi.nlm.nih.gov/pubmed/25609694 http://dx.doi.org/10.1093/nar/gkv026 |
work_keys_str_mv | AT kimminyoung zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT kohdongin zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT choiwonil zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT jeonbunam zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT jeongdeokyoon zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT kimkyungsup zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT kimkunhong zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT kimsehoon zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 AT hurmanwook zbtb2increasespdk4expressionbytranscriptionalrepressionofrelap65 |