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(Circulation Research. 2000;87:699.)
© 2000 American Heart Association, Inc.

Cellular Biology

Cyclin A Downregulation and p21^cip1 Upregulation Correlate With GATA-6–Induced Growth Arrest in Glomerular Mesangial Cells

Daisuke Nagata, Etsu Suzuki, Hiroaki Nishimatsu, Masao Yoshizumi, Toshiaki Mano, Kenneth Walsh, Masataka Sata, Masao Kakoki, Atsuo Goto, Masao Omata, Yasunobu Hirata

From the Second Department of Internal Medicine, Faculty of Medicine (D.N., E.S., M.S., M.K., A.G., M.O., Y.H.), Department of Urology, Faculty of Medicine (H.N.), Department of Geriatrics, Faculty of Medicine (M.Y.), University of Tokyo, Japan, and Division of Cardiovascular Research, St. Elizabeth’s Medical Center, Tufts University School of Medicine (T.M., K.W.), Boston, Mass.

Correspondence to Etsu Suzuki, MD, PhD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail suzuki-2im{at}h.u-tokyo.ac.jp

Abstract—The GATA-6 transcription factor is reported to be expressed in vascular myocytes. Because glomerular mesangial cells (GMCs) and vascular myocytes have similar properties, we examined whether GATA-6 was expressed in cultured GMCs and whether overexpression of GATA-6 induced cell cycle arrest in GMCs, using a recombinant adenovirus that expresses GATA-6 (Ad GATA-6). GATA-6 expression in GMCs was downregulated when quiescent GMCs were stimulated by serum to reenter the cell cycle. [³H]thymidine uptake was inhibited in GMCs infected with Ad GATA-6 in a dose- and time-dependent manner. The expression of cyclin A protein was decreased and that of the cyclin-dependent kinase inhibitor p21^cip1 was increased in GMCs infected with Ad GATA-6. Although the expression of p21^cip1 transcripts did not change remarkably, p21^cip1 protein was stabilized in GMCs infected with Ad GATA-6, suggesting a post-transcriptional regulation of p21^cip1 expression. Northern blot analysis showed that expression of the cyclin A transcript was decreased in Ad GATA-6–infected cells, whereas this decrease of cyclin A was not observed in GMCs derived from p21^cip1 null mice. Our results demonstrate that GATA-6 is endogenously expressed in GMCs and that overexpression of GATA-6 can induce cell cycle arrest. Our results also show that GATA-6–induced cell cycle arrest is associated with inhibition of cyclin A expression and p21^cip1 upregulation. Finally, our results indicate that the GATA-6–induced suppression of cyclin A expression depends on the presence of p21^cip1.

Key Words: cell cycle • transcription factors • kidney • gene transfer • cyclin-dependent kinases

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