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Molecular and Cellular Biology, May 2007, p. 3489-3498, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00665-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Phosphorylation of the Cyclic AMP Response Element Binding Protein Mediates Transforming Growth Factor ß-Induced Downregulation of Cyclin A in Vascular Smooth Muscle Cells{triangledown}

Kentaro Kamiya,1,{ddagger} Kenji Sakakibara,1,{dagger},{ddagger} Evan J. Ryer,1 Raymond P. Hom,1 Edward B. Leof,2 K. Craig Kent,1 and Bo Liu1*

Department of Surgery, Division of Vascular Surgery, Weill Medical College of Cornell University, New York, New York 10021,1 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota2

Received 17 April 2006/ Returned for modification 17 May 2006/ Accepted 9 February 2007

Transforming growth factor ß (TGFß), a multifunctional cytokine associated with vascular injury, is a potent inhibitor of cell proliferation. The current results demonstrate that the TGFß-induced growth arrest of vascular smooth muscle cells (VSMCs) is associated with cyclin A downregulation. TGFß represses the cyclin A gene through a cyclic AMP (cAMP) response element, which complexes with the cAMP response element binding protein (CREB). The CREB-cyclin A promoter interaction is hindered by TGFß, preceded by a TGFß receptor-dependent CREB phosphorylation. Induction of CREB phosphorylation with forskolin or 6bnz-cAMP mimics TGFß's inhibitory effect on cyclin A expression. Conversely, inhibition of CREB phosphorylation with a CREB mutant in which the phosphorylation site at serine 133 was changed to alanine (CREB-S133A) upregulated cyclin A gene expression. Furthermore, the CREB-S133A mutant abolished TGFß-induced CREB phosphorylation, cyclin A downregulation, and growth inhibition. Since we have previously shown that the novel PKC isoform protein kinase C delta (PKC{delta}) is activated by TGFß in VSMCs, we tested the role of this kinase in CREB phosphorylation and cyclin A downregulation. Inhibition of PKC{delta} by a dominant-negative mutant or by targeted gene deletion blocked TGFß-induced CREB phosphorylation and cyclin A downregulation. Taken together, our data indicate that phosphorylation of CREB stimulated by TGFß is a critical step leading to the inhibition of cyclin A expression and, thus, VSMC proliferation.

* Corresponding author. Mailing address: Department of Surgery, Weill Cornell Medical College, 525 East 68th Street, Room P707, New York, NY 1002. Phone: (212) 746-2440. Fax: (212) 746-5812. E-mail: bol2001{at}med.cornell.edu

{triangledown} Published ahead of print on 26 February 2007.

{ddagger} K. Kamiya and K. Sakakibara contributed equally to this work.

{dagger} Present address: Second Department of Surgery, Yamanashi University, Faculty of Medicine, Yamanashi, Japan.

Molecular and Cellular Biology, May 2007, p. 3489-3498, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00665-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tsai, S., Hollenbeck, S. T., Ryer, E. J., Edlin, R., Yamanouchi, D., Kundi, R., Wang, C., Liu, B., Kent, K. C. (2009). TGF-{beta} through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am. J. Physiol. Heart Circ. Physiol. 297: H540-H549 [Abstract] [Full Text]  


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