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

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. [H]thymidine uptake was inhibited in GMCs infected with Ad GATA-6 in a doseand time-dependent manner. The expression of cyclin A protein was decreased and that of the cyclin-dependent kinase inhibitor p21 was increased in GMCs infected with Ad GATA-6. Although the expression of p21 transcripts did not change remarkably, p21 protein was stabilized in GMCs infected with Ad GATA-6, suggesting a post-transcriptional regulation of p21 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 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 upregulation. Finally, our results indicate that the GATA-6–induced suppression of cyclin A expression depends on the presence of p21. (Circ Res. 2000;87:699-704.)