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Up-regulation of acetyl-CoA carboxylase α and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells

 Sarah Yoon  ;  Min-Young Lee  ;  Kyung-Sup Kim  ;  Byeong-Woo Park  ;  Yong-Ho Ahn  ;  Yoo-Kyung Koh  ;  Jong-Seok Moon  ;  Sahng Wook Park 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.282(36) : 26122-26131, 2007 
Journal Title
Issue Date
3' Untranslated Regions/genetics ; 3' Untranslated Regions/metabolism ; 5' Untranslated Regions/genetics ; 5' Untranslated Regions/metabolism ; Acetyl-CoA Carboxylase/biosynthesis* ; Acetyl-CoA Carboxylase/genetics ; Breast Neoplasms/enzymology* ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Chromones/pharmacology ; Enzyme Induction/drug effects ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Fatty Acid Synthases/biosynthesis* ; Fatty Acid Synthases/genetics ; Female ; Gene Expression Regulation, Neoplastic*/drug effects ; Humans ; Morpholines/pharmacology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Biosynthesis*/drug effects ; Protein Kinases/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism* ; Signal Transduction*/drug effects ; Sterol Regulatory Element Binding Protein 1/genetics ; Sterol Regulatory Element Binding Protein 1/metabolism ; TOR Serine-Threonine Kinases
Expression of the HER2 oncogene is increased in ∼30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase α (ACCα) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACCα compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACCα in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACCα, and the HER2-mediated increase in ACCα and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACCα. On the other hand, FASN and ACCα were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5′- and 3′-untranslated regions of both FASN and ACCα mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACCα in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Koh, Yoo Kyung(고유경)
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Park, Byeong Woo(박병우) ORCID logo https://orcid.org/0000-0003-1353-2607
Park, Sahng Wook(박상욱) ORCID logo https://orcid.org/0000-0002-9594-7074
Ahn, Yong Ho(안용호) ORCID logo https://orcid.org/0000-0002-4133-0757
Yoon, Sa Rah(윤사라)
Lee, Min Young(이민영)
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