Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor
SMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as <i>p21WAF1</i> and <i>p15INK4b</i>...
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doaj-dac5a3fef66845329ef7f5cf56577e812021-06-01T01:04:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01225595559510.3390/ijms22115595Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional CofactorNirmal Rajasekaran0Kyoung Song1Jin-Hee Lee2Yun Wei3Özgür Cem Erkin4Hunseok Lee5Young-Kee Shin6Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, KoreaCollege of Pharmacy, Duksung Women’s University, Seoul 01369, KoreaLaboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, KoreaLaboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, KoreaDepartment of Bioengineering, Faculty of Engineering, Adana Science and Technology, Adana 01250, TurkeyLaboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, KoreaLaboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, KoreaSMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as <i>p21WAF1</i> and <i>p15INK4b</i> through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of <i>SMAD4</i> could be related to tumorigenesis or malignancy progression. However, in some cancer types, <i>SMAD4</i> is neither mutated nor deleted. In the current study, we demonstrate that TGF-β signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-β/SMAD4-induced <i>p15INK4b</i> mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the <i>SMAD4</i> promoter, thereby decreasing <i>SMAD4</i> mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-β/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-β/SMAD4-signaling suppression in tumorigenesis.https://www.mdpi.com/1422-0067/22/11/5595NRF1SMAD4transforming growth factor-βp15INK4btumor suppression |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nirmal Rajasekaran Kyoung Song Jin-Hee Lee Yun Wei Özgür Cem Erkin Hunseok Lee Young-Kee Shin |
spellingShingle |
Nirmal Rajasekaran Kyoung Song Jin-Hee Lee Yun Wei Özgür Cem Erkin Hunseok Lee Young-Kee Shin Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor International Journal of Molecular Sciences NRF1 SMAD4 transforming growth factor-β p15INK4b tumor suppression |
author_facet |
Nirmal Rajasekaran Kyoung Song Jin-Hee Lee Yun Wei Özgür Cem Erkin Hunseok Lee Young-Kee Shin |
author_sort |
Nirmal Rajasekaran |
title |
Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor |
title_short |
Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor |
title_full |
Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor |
title_fullStr |
Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor |
title_full_unstemmed |
Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor |
title_sort |
nuclear respiratory factor-1, a novel smad4 binding protein, represses tgf-β/smad4 signaling by functioning as a transcriptional cofactor |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-05-01 |
description |
SMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as <i>p21WAF1</i> and <i>p15INK4b</i> through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of <i>SMAD4</i> could be related to tumorigenesis or malignancy progression. However, in some cancer types, <i>SMAD4</i> is neither mutated nor deleted. In the current study, we demonstrate that TGF-β signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-β/SMAD4-induced <i>p15INK4b</i> mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the <i>SMAD4</i> promoter, thereby decreasing <i>SMAD4</i> mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-β/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-β/SMAD4-signaling suppression in tumorigenesis. |
topic |
NRF1 SMAD4 transforming growth factor-β p15INK4b tumor suppression |
url |
https://www.mdpi.com/1422-0067/22/11/5595 |
work_keys_str_mv |
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