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RISS 인기검색어
- 검색키워드
- 저자 : Chawnshang Chang (검색결과 5 건)
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김승진,김응석,최호중,박성수,Chawnshang Chang 한국분자세포생물학회 2011 Molecules and cells Vol.31 No.4
Stearoyl-CoA desaturase (SCD), the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids, is highly expressed in prostate cancer although the SCD protein has been known to be rapidly turned over by proteolytic cleavage. The present data demonstrate that SCD can promote proliferation of androgen receptor (AR)-positive LNCaP prostate cancer cells and enhance dihydrotestosterone (DHT)-induced AR transcriptional activity, resulting in increased expression of prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (KLK2). Interestingly, among the previously reported SCD-derived peptides produced by proteolytic cleavage of SCD, a peptide spanning amino acids 130-162 of SCD (SCD-CoRNR) contained the CoRNR box motif (LFLII) and enhanced AR transcriptional activity. In contrast, a mutant SCD-CoRNR in which Leu136 was replaced by Ala had no effect on AR transcriptional activity. Moreover, SCD-CoRNR directly interacted with AR and inhibited RIP140 suppression of AR transactivation. Knockdown of the SCD gene by SCD microRNA suppressed AR transactivation with decreased cell proliferation, suggesting that SCD may regulate the proliferation of LNCaP cells via modulation of AR transcriptional activity. Moreover, ectopic expression of SCD in LNCaP cells facilitated LNCaP tumor formation and growth in nude mice. Together, the data indicate that SCD plays a key role in the regulation of AR transcriptional activity in prostate cancer cells.
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TR4 activates FATP1 gene expression to promote lipid accumulation in 3T3-L1 adipocytes
Choi, Hojung,Kim, Seung-Jin,Park, Sung-Soo,Chang, Chawnshang,Kim, Eungseok Elsevier 2011 FEBS letters Vol.585 No.17
<P><B>Highlights</B></P><P>► TR4 enhances fatty acid uptake in 3T3-L1 adipocytes via induction of the FATP1 gene. ► Knockdown of FATP1 abolished TR4-enhanced fatty acid uptake in 3T3-L1 adipocytes. ► TR4 facilitates lipid accumulation in 3T3-L1 adipocytes. ► Silencing of TR4 in adipocytes reduced FATP1 expression and lipid accumulation.</P> <P><B>Abstract</B></P><P>We show that TR4 facilitates lipid accumulation in 3T3-L1 adipocytes via induction of the FATP1 gene. Further study showed that TR4 transactivated FATP1 5′ promoter activity via direct binding to the TR4 responsive element located at the FATP1 5′ promoter region. Constitutive overexpression of TR4 in 3T3-L1 adipocytes resulted in increased lipid accumulation, accompanied by an increase in fatty acid uptake. However, small interfering RNA knockdown of FATP1 abolished TR4-enhanced fatty acid uptake. Moreover, microRNA-mediated silencing of TR4 in 3T3-L1 adipocytes drastically reduced basal FATP1 5′ promoter activity and FATP1 expression with reduced lipid accumulation.</P>
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Xie, Shaozhen,Lee, Yi-Fen,Kim, Eungseok,Chen, Lu-Min,Ni, Jing,Fang, Lei-Ya,Liu, Su,Lin, Shin-Jen,Abe, Jun-Ichi,Berk, Bradford,Ho, Feng-Ming,Chang, Chawnshang National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.32
<P>Testicular orphan nuclear receptor 4 (TR4) is an orphan member of the nuclear receptor superfamily with diverse physiological functions. Using TR4 knockout (TR4(-/-)) mice to study its function in cardiovascular diseases, we found reduced cluster of differentiation (CD)36 expression with reduced foam cell formation in TR4(-/-) mice. Mechanistic dissection suggests that TR4 induces CD36 protein and mRNA expression via a transcriptional regulation. Interestingly, we found this TR4-mediated CD36 transactivation can be further enhanced by polyunsaturated fatty acids (PUFAs), such as omega-3 and -6 fatty acids, and their metabolites such as 15-hydroxyeico-satetraonic acid (15-HETE) and 13-hydroxy octa-deca dieonic acid (13-HODE) and thiazolidinedione (TZD)-rosiglitazone. Both electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrate that TR4 binds to the TR4 response element located on the CD36 5'-promoter region for the induction of CD36 expression. Stably transfected TR4-siRNA or functional TR4 cDNA in the RAW264.7 macrophage cells resulted in either decreased or increased CD36 expression with decreased or increased foam cell formation. Restoring functional CD36 cDNA in the TR4 knockdown macrophage cells reversed the decreased foam cell formation. Together, these results reveal an important signaling pathway controlling CD36-mediated foam cell formation/cardiovascular diseases, and findings that TR4 transactivation can be activated via its ligands/activators, such as PUFA metabolites and TZD, may provide a platform to screen new drug(s) to battle the metabolism syndrome, diabetes, and cardiovascular diseases.</P>
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Kim, Eungseok,Liu, Ning-Chun,Yu, I-Chen,Lin, Hung-Yun,Lee, Yi-Fen,Sparks, Janet D.,Chen, Lu-Min,Chang, Chawnshang American Diabetes Association 2011 Diabetes Vol.60 No.5
<P><B>OBJECTIVE</B></P><P>TR4 is a nuclear receptor without clear pathophysiological roles. We investigated the roles of hepatic TR4 in the regulation of lipogenesis and insulin sensitivity in vivo and in vitro.</P><P><B>RESEARCH DESIGN AND METHODS</B></P><P>TR4 activity and phosphorylation assays were carried out using hepatocytes and various TR4 wild-type and mutant constructs. Liver tissues from TR4 knockout, C57BL/6, and <I>db/db</I> mice were examined to investigate TR4 target gene stearoyl-CoA desaturase (<I>SCD</I>) 1 regulation.</P><P><B>RESULTS</B></P><P>TR4 transactivation is inhibited via phosphorylation by metformin-induced AMP-activated protein kinase (AMPK) at the amino acid serine 351, which results in the suppression of SCD1 gene expression. Additional mechanistic dissection finds TR4-transactivated <I>SCD1</I> promoter activity via direct binding to the TR4-responsive element located at −243 to −255 on the promoter region. The pathophysiological consequences of the metformin→AMPK→TR4→SCD1 pathway are examined via TR4 knockout mice and primary hepatocytes with either knockdown or overexpression of TR4. The results show that the suppression of <I>SCD1</I> via loss of TR4 resulted in reduced fat mass and increased insulin sensitivity with increased β-oxidation and decreased lipogenic gene expression.</P><P><B>CONCLUSIONS</B></P><P>The pathway from metformin→AMPK→TR4→SCD1→insulin sensitivity suggests that TR4 may function as an important modulator to control lipid metabolism, which sheds light on the use of small molecules to modulate TR4 activity as a new alternative approach to battle the metabolic syndrome.</P>
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