SHD1 is a novel cytokine-inducible, negative feedback regulator of STAT5-dependent transcription.
STAT5 is a critical mediator of a variety of cytokine signaling whose transcriptional activity is regulated by associating with various proteins. During a search for STAT5-interacting proteins, we identified SHD1, a mammalian homologue of yeast gene Sac3, as a potential interacter. SHD1 was localized in the nucleus, and induced by cytokines that activate STAT5, such as erythropoietin, interleukin-2 (IL-2), or IL-3. SHD1 interacted specifically with STAT5A and STAT5B, and interestingly, it specifically repressed STAT5-dependent transcription in vitro without affecting the stability or phosphorylation of STAT5 protein. Gene disruption study revealed that T, B, or bone marrow cells from mice lacking SHD1 were hyperresponsive to T-cell-receptor engagement, or stimulation with various STAT5-activating cytokines. These results suggest that SHD1 is a novel cytokine-inducible negative feedback regulator of STAT5.
Center of Excellence, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. hnakajim@sc.itc.keio.ac.jp
Hideaki
H
Nakajima
Toshiki
T
Tamura
Miyuki
M
Ito
Fumi
F
Shibata
Kana
K
Kuroda
Yumi
Y
Fukuchi
Naohide
N
Watanabe
Toshio
T
Kitamura
Yasuo
Y
Ikeda
Makoto
M
Handa
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism*; D056504:Chromatin Assembly Factor-1; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D056504:Chromatin Assembly Factor-1; D016207:Cytokines; D004268:DNA-Binding Proteins; C061736:MSI1 protein, S cerevisiae; D012097:Repressor Proteins; C538751:SAC3D1 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D029701:Saccharomyces cerevisiae Proteins; C494093:Stat5a protein, mouse; D025521:Tumor Suppressor Proteins