RRC ID 44566
Author Nishimoto A, Kugimiya N, Hosoyama T, Enoki T, Li TS, Hamano K.
Title JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein-protein interaction in human colon cancer cells.
Journal Biochem Biophys Res Commun
Abstract Recent studies have revealed that unphosphorylated STAT3 forms a dimer, translocates to the nucleus, binds to the STAT3 binding site, and activates the transcription of STAT3 target genes, thereby playing an important role in oncogenesis in addition to phosphorylated STAT3. Among signaling steps of unphosphorylated STAT3, nuclear translocation and target DNA-binding are the critical steps for its activation. Therefore, elucidating the regulatory mechanism of these signaling steps of unphosphorylated STAT3 is a potential step in the discovery of a novel cancer drug. However, the mechanism of unphosphorylated STAT3 binding to the promoter of target genes remains unclear. In this study, we focused on Jun activation domain-binding protein 1 (JAB1) as a candidate protein that regulates unphosphorylated STAT3 DNA-binding activity. Initially, we observed that both unphosphorylated STAT3 and JAB1 existed in the nucleus of human colon cancer cell line COLO205 at the basal state (no cytokine stimulation). On the other hand, phosphorylated STAT3 did not exist in the nucleus of COLO205 cells at the basal state. Immunoprecipitation using nuclear extract of COLO205 cells revealed that JAB1 interacted with unphosphorylated STAT3. To investigate the effect of JAB1 on unphosphorylated STAT3 activity, RNAi studies were performed. Although JAB1 knockdown tended to increase nuclear STAT3 expression, it significantly decreased unphosphorylated STAT3 DNA-binding activity. Subsequently, JAB1 knockdown significantly decreased the expression levels of MDR1, NANOG, and VEGF, which are STAT3 target genes. Furthermore, the expression level of nuclear JAB1, but not nuclear STAT3, correlated with unphosphorylated STAT3 DNA-binding activity between COLO205 and LoVo cells. Taken together, these results suggest that nuclear JAB1 positively regulates unphosphorylated STAT3 DNA-binding activity through protein-protein interaction in human colon cancer cell line COLO205.
Volume 438(3)
Pages 513-8
Published 2013-8-30
DOI 10.1016/j.bbrc.2013.07.105
PII S0006-291X(13)01279-5
PMID 23911788
MeSH COP9 Signalosome Complex Cell Line, Tumor Cell Nucleus / metabolism Colonic Neoplasms / metabolism DNA / metabolism* Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / physiology* Peptide Hydrolases / genetics Peptide Hydrolases / physiology* Phosphorylation RNA Interference STAT3 Transcription Factor / biosynthesis STAT3 Transcription Factor / metabolism*
IF 2.705
Times Cited 16
Human and Animal Cells