Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-?/SMAD4 Signaling by Functioning as a Transcriptional Cofactor

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dc.authoridRajasekaran, Nirmal/0000-0001-7400-4387
dc.contributor.authorRajasekaran, Nirmal
dc.contributor.authorSong, Kyoung
dc.contributor.authorLee, Jin-Hee
dc.contributor.authorWei, Yun
dc.contributor.authorErkin, Ozgur Cem
dc.contributor.authorLee, Hunseok
dc.contributor.authorShin, Young-Kee
dc.date.accessioned2025-01-06T17:43:48Z
dc.date.available2025-01-06T17:43:48Z
dc.date.issued2021
dc.description.abstractSMAD4, a key regulator of transforming growth factor-beta (TGF-beta) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-beta /SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as p21WAF1 and p15INK4b through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of SMAD4 could be related to tumorigenesis or malignancy progression. However, in some cancer types, SMAD4 is neither mutated nor deleted. In the current study, we demonstrate that TGF-beta 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-beta /SMAD4-induced p15INK4b mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter, thereby decreasing SMAD4 mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-beta /SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-beta /SMAD4-signaling suppression in tumorigenesis.
dc.description.sponsorshipBasic Science Research Program through the National Research Foundation of Korea - Ministry of Education [2016R1A6A1A03007648]
dc.description.sponsorshipThis research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2016R1A6A1A03007648).
dc.identifier.doi10.3390/ijms22115595
dc.identifier.issn1422-0067
dc.identifier.issue11
dc.identifier.pmid34070531
dc.identifier.urihttps://doi.org/10.3390/ijms22115595
dc.identifier.urihttps://hdl.handle.net/20.500.14669/2808
dc.identifier.volume22
dc.identifier.wosWOS:000660235200001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherMdpi
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241211
dc.subjectNRF1
dc.subjectSMAD4
dc.subjecttransforming growth factor-beta
dc.subjectp15INK4b
dc.subjecttumor suppression
dc.titleNuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-?/SMAD4 Signaling by Functioning as a Transcriptional Cofactor
dc.typeArticle

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