All-trans retinoic acid inhibits vascular smooth muscle cell proliferation targeting multiple genes for cyclins and cyclin-dependent kinases

C. Kosaka, T. Sasaguri, Y. Komiyama, H. Takahashi

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Retinoids have been shown to promote vascular smooth muscle cell differentiation, although the underlying mechanism is unclear. In fact, treatment of rat aortic smooth muscle cells with all-trans retinoic acid (ATRA) has been shown to markedly elevate the mRNA and protein levels of smooth muscle α-actin. Considering that an exit from the cell cycle is a prerequisite for cell differentiation, we examined the effect of ATRA on cellular events during the progression from G0 to S phase. Pretreatment with ATRA dose-dependently inhibited DNA synthesis induced by basic fibroblast growth factor. However, ATRA did not inhibit transient activation of mitogen-activated protein kinase (MAPK) in response to mitogenic stimulation. And ATRA consistently failed to influence the phosphorylation of MAPK kinase (MEK) and the expression of MAPK-specific dual phosphatase (MKP-1). ATRA did not interfere with other early mitogenic signals either, such as the phosphorylation of FGF-1 receptor or the induction of immediate early genes c-fos, c-jun, and c-myc. In contrast, ATRA strongly suppressed the pRb kinase activities of the cyclin-dependent kinases (Cdks) Cdk4, Cdk6, and Cdk2. ATRA did not influence the expressions of Cip/Kip family Cdk inhibitors or those of cyclins D1 and D2, whereas it strongly inhibited the expressions of cyclins D3 and E, Cdk4, Cdk6, and Cdk2. These results suggest that ATRA targets multiple genes essential for entry into the cell cycle and for the subsequent progression to G1 phase, but without interrupting early mitogenic signals upstream of MAPK.

Original languageEnglish
Pages (from-to)579-588
Number of pages10
JournalHypertension Research
Volume24
Issue number5
DOIs
Publication statusPublished - Nov 21 2001

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Cyclins
Gene Targeting
Cyclin-Dependent Kinases
Tretinoin
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Proliferation
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Cell Differentiation
Cell Cycle
Dual Specificity Phosphatase 1
Phosphorylation
Cyclin D3
Cyclin D2
Cyclin-Dependent Kinase 4
Fibroblast Growth Factor 1
Fibroblast Growth Factor Receptors
Cyclin E
Immediate-Early Genes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

All-trans retinoic acid inhibits vascular smooth muscle cell proliferation targeting multiple genes for cyclins and cyclin-dependent kinases. / Kosaka, C.; Sasaguri, T.; Komiyama, Y.; Takahashi, H.

In: Hypertension Research, Vol. 24, No. 5, 21.11.2001, p. 579-588.

Research output: Contribution to journalArticle

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