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GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression

Martin F. Crook^*, Michelle Olive^*, Hai-Hui Xue^,1, Thomas H. Langenickel^*, Manfred Boehm^*, Warren J. Leonard and Elizabeth G. Nabel^*,2

^* Cardiovascular Branch and

Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

²Correspondence: National Heart, Lung, and Blood Institute, Bldg. 31/Rm. 5A48, 31 Center Dr., Bethesda, MD 20892, USA; E-mail: nabele{at}nih.gov

The cyclin-dependent kinase inhibitor p27^Kip1 arrests cell cycle progression through G1/S phases and is regulated by phosphorylation of serine/threonine residues. Recently, we identified the serine/threonine kinase, KIS, which phosphorylates p27^Kip1 on serine 10 leading to nuclear export of p27^Kip1 and protein degradation. However, the molecular mechanisms of transcriptional activation of the human KIS gene and its biological activity are not known. We mapped the transcription initiation site 116 bp 5' to the translation start site, and sequences extending to –141 were sufficient for maximal promoter activity. Mutation in either of two Ets-binding sites in this region resulted in an approximately 75–80% decrease in promoter activity. These sites form at least 3 specific complexes, which contained GA-binding protein (GABP). Knocking down GABP by siRNA in vascular smooth muscle cells (VSMCs) diminished KIS gene expression and reduced cell migration. Correspondingly, in serum stimulated GABP-deficient mouse embryonic fibroblasts (MEFs), KIS gene expression was also significantly reduced, which was associated with an increase in p27^Kip1 protein levels and a decreased percentage of cells in S-phase. Consistent with these findings, following vascular injury in vivo, GABP-heterozygous mice demonstrated reduced KIS gene expression within arterial lesions and these lesions were significantly smaller compared to GABP^+/+ mice. In summary, serum-responsive GABP binding to Ets-binding sites activates the KIS promoter, leading to KIS gene expression, cell migration, and cell cycle progression.—Crook, M. F., Olive, M., Xue, H.-H., Langenickel, T. H., Boehm, M., Leonard, W. J., Nabel, E. G. GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression.

Key Words: kinase interacting strathmin • p27^Kip1 • vascular smooth muscle cells • vascular biology