Neil Clipstone, PhD

  • Associate Professor
  • Molecular Pharmacology and Therapeutics

The role of the calcineurin/NFAT-signaling pathway in cell growth and differentiation

The primary research interest of our laboratory is focused on understanding the regulation and function of the calcineurin/NFAT-signaling pathway. The pathway is comprised of the calcium-regulated serine/threonine phosphatase calcineurin and its direct downstream effectors, the members of the NFAT family of latent transcription factors. In response to receptor-induced increases in the intracellular calcium concentration, calcineurin is activated and directly binds and dephosphorylates latent NFAT proteins present in the cytoplasm. This calcineurin-mediated dephosphorylation promotes the activation of NFAT proteins, inducing their entry into the nucleus, where they bind to their cognate DNA target sequences and activate the transcription of specific genes. We are particularly interested in determining how the activation of this exquisitely calcium-sensitive signaling pathway serves to couple ligand-induced dynamic changes in the intracellular calcium concentration into corresponding changes in gene expression that ultimately act to influence changes in cell growth and differentiation. Although perhaps best known for its role in the regulation of the immune response, it has become increasingly apparent that the calcineurin/NFAT-signaling pathway also performs important functional roles in a diverse array of non-immune system cells and tissues. Indeed, our recent studies have identified a number of novel previously unappreciated roles for this pathway in the regulation of a variety of distinct cell fate decisions including adipocyte differentiation, osteoclastogenesis and cell transformation. Accordingly, we are currently using a combination of in vitro molecular, biochemical and genetic techniques, together with a number of in vivo transgenic and gene knockout mouse approaches, to investigate the role of the calcineurin/NFAT-signaling pathway in these various biological processes. Current ongoing projects include: 1. Delineating the role of the calcineurin/NFAT-signaling pathway in the regulation of adipocyte differentiation and function, and determining its potential role in the development of obesity and type-2 diabetes. 2. Investigating the role of the calcineurin/NFAT-signaling pathway in cell transformation and the development of cancer. By fully delineating the molecular mechanisms underlying the distinct functional effects of the calcineurin/NFAT-signaling pathway in these biological processes, we hope to gain important molecular insights into the role of the calcineurin/NFAT-signaling pathway in the calcium-dependent regulation of cell growth and differentiation.

  • Annamalai,D.; Clipstone,N. A.Prostaglandin F2alpha inhibits adipogenesis via an autocrine-mediated interleukin-11/glycoprotein 130/STAT1-dependent signaling cascade Journal of cellular biochemistry 2014 ;115(7):1308-1321
  • Lagunas,L.; Clipstone,N. A.Deregulated NFATc1 activity transforms murine fibroblasts via an autocrine growth factor-mediated Stat3-dependent pathway. Journal of cellular biochemistry 2009 ;108(1):237-248
  • Liu,L.; Clipstone,N. A.Prostaglandin F2alpha induces the normoxic activation of the hypoxia-inducible factor-1 transcription factor in differentiating 3T3-L1 preadipocytes: Potential role in the regulation of adipogenesis. Journal of cellular biochemistry 2008 ;105(1):89-98
  • Liu,L.; Clipstone,N. A.Prostaglandin F2alpha inhibits adipocyte differentiation via a G alpha q-calcium-calcineurin-dependent signaling pathway. Journal of cellular biochemistry 2007 ;100(1):161-173
  • Helms,W. S.; Jeffrey,J. L.; Holmes,D. A.; Townsend,M. B.; Clipstone,N. A.; Su,L.Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells. Journal of leukocyte biology 2007 ;82(2):361-369
  • Koltsova,E. K.; Ciofani,M.; Benezra,R.; Miyazaki,T.; Clipstone,N.; Zuniga-Pflucker,J. C.; Wiest,D. L.Early growth response 1 and NF-ATc1 act in concert to promote thymocyte development beyond the beta-selection checkpoint. Journal of Immunology 2007 ;179(7):4694-4703
  • Hirotani,H.; Tuohy,N. A.; Woo,J. T.; Stern,P. H.; Clipstone,N. A.The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. Journal of Biological Chemistry 2004 ;279(14):13984-13992