Selective inhibition of the function of tyrosine-phosphorylated STAT3 with a phosphorylation site-specific intrabody

Mi Young Koo; Jiyoung Park; Jung Mi LimSei Yoon JooSeung-Pil ShinHyun Bo ShimJunho ChungDongmin KangHyun Ae WooSue Goo Rhee

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Selective inhibition of the function of tyrosine-phosphorylated STAT3 with a phosphorylation site-specific intrabody

机译：Selective inhibition of the function of tyrosine-phosphorylated STAT3 with a phosphorylation site-specific intrabody

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Signal transducer and activator of transcription 3 (STAT3) is a multifunctional protein that participates in signaling pathways initiated by various growth factors and cytokines. It exists in multiple forms including those phosphorylated on Tyr~(705) (pYSTAT3) or Ser~(727) (pSSTAT3) as well as the unphosphorylated protein(USTAT3). In addition to the canonical transcriptional regulatory role of pYSTAT3, both USTAT3 and pSSTAT3 function as transcriptional regulators by binding to distinct promoter sites and play signaling roles in the cytosol or mitochondria. The roles of each STAT3 species in different biological processes have not been readily amenable to investigation, however. We have now prepared an intrabody that binds specifically and with high affinity to the tyrosinephosphorylated site of pYSTAT3. Adenovirus-mediated expression of the intrabody in HepG2 cells as well as mouse liver blocked both the accumulation of pYSTAT3 in the nucleus and the production of acute phase response proteins induced by interleukin-6. Intrabody expression did not affect the overall accumulation of pSSTAT3 induced by interleukin-6 or phorbol 12-myristate 13-acetate (PMA), the PMA-induced expression of the c-Fos gene, or the PMA-induced accumulation of pSSTAT3 specifically in mitochondria. In addition, it had no effect on interleukin-6–induced expression of the gene for IFN regulatory factor 1, a downstream target of STAT1. Our results suggest that the engineered intrabody is able to block specifically the downstream effects of pYSTAT3 without influencing those of pSSTAT3, demonstrating the potential of intrabodies as tools to dissect the cellular functions of specific modified forms of proteins that exist as multiple species.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第17期|6269-6274|共6页
作者
Mi Young Koo; Jiyoung Park; Jung Mi LimSei Yoon JooSeung-Pil ShinHyun Bo ShimJunho ChungDongmin KangHyun Ae WooSue Goo Rhee;
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作者单位

Division of Life and Pharmaceutical Sciences,Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea;

Graduate School of Pharmaceutical Sciences,Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Korea;

Genitourinary Cancer Branch, Research Institute National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, KoreaDepartment of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 28 Yeongun-dong, Jongro-gu, Seoul 110-799, KoreaYonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
accumulation; expression; investigation;

Selective inhibition of the function of tyrosine-phosphorylated STAT3 with a phosphorylation site-specific intrabody

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