Cyclin A downregulation and p21(cip1) 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. [(3)H]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).