Down-regulation of the cyclin a promoter by transforming growth factor- β1 is associated with a reduction in phosphorylated activating transcription factor-1 and cyclic AMP-responsive element-binding protein

Masao Yoshizumi, Hong Wang, Chung Ming Hsieh, Nicholas E.S. Sibinga, Mark A. Perrella, Mu En Lee

Research output: Contribution to journalArticle

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Abstract

Transforming growth factor (TGF)-β1 prevents cell cycle progression by inhibiting several regulators, including cyclin A. To study the mechanisms by which TGF-β1 down-regulates cyclin A gene expression, we transfected reporter plasmids driven by the cyclin A promoter into mink lung epithelial cells in the absence and presence of TGF-β1. The TGF-β1-induced down- regulation of cyclin A promoter activity appeared to be mediated via the activating transcription factor (ATF) site, because mutation of this site abolished down-regulation. Surprisingly, although TGF-β1 treatment for 24 h markedly decreased cyclin A promoter activity, it did not decrease the abundance of the ATF-binding proteins ATF-1 and cyclic AMP-responsive binding protein (CREB). However, we detected 90 and 78% reductions (by Western analysis) in phosphorylated CREB and ATF-1, respectively, in mink lung epithelial cells treated with TGF-β1. TGF-β1-induced down-regulation of cyclin A promoter activity was reversed by okadaic acid (a phosphatase inhibitor) and by cotransfection with plasmids expressing the cAMP-dependent protein kinase catalytic subunit or the simian virus small tumor antigen (Sm- t, an inhibitor of PP2A). These data indicate that TGF-β1 may down-regulate cyclin A promoter activity by decreasing phosphorylation of CREB and ATF-1.

Original languageEnglish (US)
Pages (from-to)22259-22264
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number35
DOIs
StatePublished - Aug 29 1997
Externally publishedYes

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Activating Transcription Factor 1
Cyclins
Cyclin A
Transforming Growth Factors
Cyclic AMP
Carrier Proteins
Down-Regulation
Activating Transcription Factors
Mink
Plasmids
Epithelial Cells
Okadaic Acid
Lung
Phosphorylation
Neoplasm Antigens
Acid Phosphatase
Cyclic AMP-Dependent Protein Kinases
Viruses
Phosphoric Monoester Hydrolases
Gene expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Down-regulation of the cyclin a promoter by transforming growth factor- β1 is associated with a reduction in phosphorylated activating transcription factor-1 and cyclic AMP-responsive element-binding protein. / Yoshizumi, Masao; Wang, Hong; Hsieh, Chung Ming; Sibinga, Nicholas E.S.; Perrella, Mark A.; Lee, Mu En.

In: Journal of Biological Chemistry, Vol. 272, No. 35, 29.08.1997, p. 22259-22264.

Research output: Contribution to journalArticle

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abstract = "Transforming growth factor (TGF)-β1 prevents cell cycle progression by inhibiting several regulators, including cyclin A. To study the mechanisms by which TGF-β1 down-regulates cyclin A gene expression, we transfected reporter plasmids driven by the cyclin A promoter into mink lung epithelial cells in the absence and presence of TGF-β1. The TGF-β1-induced down- regulation of cyclin A promoter activity appeared to be mediated via the activating transcription factor (ATF) site, because mutation of this site abolished down-regulation. Surprisingly, although TGF-β1 treatment for 24 h markedly decreased cyclin A promoter activity, it did not decrease the abundance of the ATF-binding proteins ATF-1 and cyclic AMP-responsive binding protein (CREB). However, we detected 90 and 78{\%} reductions (by Western analysis) in phosphorylated CREB and ATF-1, respectively, in mink lung epithelial cells treated with TGF-β1. TGF-β1-induced down-regulation of cyclin A promoter activity was reversed by okadaic acid (a phosphatase inhibitor) and by cotransfection with plasmids expressing the cAMP-dependent protein kinase catalytic subunit or the simian virus small tumor antigen (Sm- t, an inhibitor of PP2A). These data indicate that TGF-β1 may down-regulate cyclin A promoter activity by decreasing phosphorylation of CREB and ATF-1.",
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