cAMP response element-binding protein mediates thrombin-induced proliferation of vascular smooth muscle cells

Tomotake Tokunou, Toshihiro Ichiki, Kotaro Takeda, Yuko Funakoshi, Naoko Iino, Akira Takeshita

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. Although recent reports have suggested that cAMP response element-binding protein (CREB) is necessary for the survival of neuronal cells, the role of CREB in VSMC proliferation is not determined. We examined the role of CREB in thrombin-induced VSMC proliferation and the effect of thrombin on phosphorylation of CREB at Ser133, which is a critical marker for activation by Western blot analysis. Thrombin induced phosphorylation of CREB in a dose-dependent manner. An oligopeptide, SFLLRN, which activates the thrombin receptor, also induced the phosphorylation of CREB. Inhibition of extracellular signal-regulated protein kinase or inhibition of p38 mitogen-activated protein kinase suppressed the thrombin-induced CREB phosphorylation. Inhibition of the epidermal growth factor receptor by AG1478 also inhibited the thrombin-induced CREB phosphorylation. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced c-fos mRNA expression and incorporation of [3H]thymidine and [3H]leucine. These results suggest that CREB-dependent gene transcription plays a critical role in thrombin-induced proliferation and hypertrophy of VSMCs. Transactivation of the epidermal growth factor receptor and 2 mitogen-activated protein kinase pathways are involved in this process. CREB may be a novel transcription factor mediating the vascular remodeling process induced by thrombin.

Original languageEnglish
Pages (from-to)1764-1769
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number11
Publication statusPublished - 2001

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


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