Physical and functional interactions between STAT3 and KAP1.
Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation and survival in immune responses, hematopoiesis, neurogenesis and other biological processes. For example, STAT3 has been reported to be constitutively activated in numerous cancer cells. To clarify the molecular mechanisms underlying the STAT activation, we performed yeast two-hybrid screening and identified KAP1/TIF1beta as a novel STAT-binding partner. KAP1 is a universal corepressor protein for the Kruppel-associated box zinc-finger protein superfamily of transcriptional repressors. We found endogenous KAP1 associated with endogenous STAT3 in vivo. Importantly, small-interfering RNA-mediated reduction of KAP1 expression enhanced interleukin (IL)-6-induced STAT3-dependent transcription and gene expression. Furthermore, reduction of KAP1 expression resulted in the marked accumulation of STAT3 phosphorylated on Ser727 in the nucleus, a modification that regulates its transcriptional activation. These results indicate that KAP1 may serve as a transcriptional regulator of the IL-6/STAT3 signaling pathway.
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
R
R
Tsuruma
N
N
Ohbayashi
S
S
Kamitani
O
O
Ikeda
N
N
Sato
R
R
Muromoto
Y
Y
Sekine
K
K
Oritani
T
T
Matsuda
D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D000076183:Tripartite Motif-Containing Protein 28; D020798:Two-Hybrid System Techniques
D009687:Nuclear Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28