NFATc2-Mediated Repression of Cyclin-Dependent Kinase 4 Expression

Abstract

to be distinct from the other NFAT isoforms (Lopez-2 Department of Adult Oncology Rodriguez et al., 1999; Miyakawa et al., 1999; Trama et The Dana-Farber Cancer Institute al., 2000). Harvard Medical School It has been extensively demonstrated that NFATc1, Boston, Massachusetts 02115 c2, and c3 require the continued activation of calcineurin 3 AMC Cancer Research Center and (Loh et al., 1996) and AP-1 elements (Macian et al., Donald Monk Cancer Research Foundation 2001) in order to regulate the production of numerous Denver, Colorado 80214 lymphokine elements. Calcineurin functions to dephos-4 University of Colorado Cancer Center phorylate serine/threonine residues within the amino Denver, Colorado 80262 terminus of NFAT, allowing NFAT to translocate to the 5 Skirball Institute of Biomolecular Medicine nucleus and bind to DNA. Inhibition of the phosphatase New York University School of Medicine activity of calcineurin by FK506 or cyclosporin A (CsA) New York, New York 10016 results in the relocalization of NFAT to the cytosol and loss of the ability to bind to DNA (Kiani et al., 2000). Targeted disruption of NFATc2 (Xanthoudakis et al., Summary 1996), NFATc1 (Ranger et al., 1998), and NFATc3 (Oukka et al., 1998) has confirmed the roles played by NFAT The calcineurin-regulated transcription factor, nuclear family members in lymphocyte development and proliffactor of activated T cells (NFAT), controls many aseration. However, targeted disruption of calcineurin A␣ pects of T cell function. Here, we demonstrate that did not reveal dramatic changes in overall T cell function the calcineurin/NFAT pathway negatively regulates and showed only slight impairment in antigen-depenthe expression of cyclin-dependent kinase 4 (CDK4). dent responses (Zhang et al., 1996). This was unex-A canonical NFAT binding site was identified and found pected given that calcineurin A␣ accounts for 70%-80% to be sensitive to calcium signals, FK506/CsA, and of the overall phosphatase activity of T cells in the pehistone deacetylase activity and to not require AP-1. riphery (Jiang et al., 1997). The ␤ form of calcineurin Ectopic expression of NFATc2 inhibited the basal acaccounts for the remaining 20%-30% of calcineurin activity of the human CDK4 promoter. Additionally, both tivity in the periphery and is thought to be more imporcalcineurin A␣ Ϫ/Ϫ and NFATc2 Ϫ/Ϫ mice had elevated tant in influencing thymocyte activation and negative protein levels of CDK4, confirming a negative regulaselection (Hollander et al., 1994; Jiang et al., 1997). The tory role for the calcineurin/NFAT pathway. This pathremaining isoform of calcineurin, ␥, is testis specific and way may thus regulate the expression of CDK4 at the does not contribute to lymphocyte function (11). transcriptional level and control how cells re-enter a CDK4 functions as an important G0/G1 restriction resting, nonproliferative state. point kinase to allow cells to leave the resting state and commit to entrance into the cell cycle (Ladha et al.,

Protein Expression Profiling Identifies Cyclophilin A as a Molecular Target in Fhit-Mediated Tumor Suppression

“…Cyclophilin A is also known to promote calcineurindependent G 1 -S transition by up-regulating cyclin D1 expression and Cdk4 activity in late G 1 phase (21)(22)(23). We confirmed up-regulation of both cyclin D1 and Cdk4 expression by cyclophilin A (10 ng/mL) treatment 60 minutes after exposure in synchronized H1299 cells; however, in the cyclophilin Amediated G 1 -S transition, there was no significant change in p21 WAF1 expression levels (Fig.…”

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

“…[8][9][10][11] It has been shown that NFAT1 directly binds specific sites at the CDK4 and Cyclin A2 promoters and negatively regulates the expression of both genes, suggesting an inhibitory role for NFAT1 in cell cycle progression. 8,9 However, the role of NFAT1 protein in cell cycle regulation of B lymphocytes has not been fully addressed. Here, we show that NFAT1 deficiency causes Cyclin E1 and E2 overexpression at the mRNA level in B cells, which is followed by increased protein levels (Fig.…”

“…3,4 Besides the canonical cytokines and cell surface markers regulated by NFAT transcription factors, several reports have shown that NFAT proteins control the activity of promoter and enhancer regions of many other inducible genes, such as FasL, Cox-2, and Vegf. [5][6][7] NFAT transcription factors have also been shown to regulate the expression of cell cycle-related genes, such as Cdk-4, Cyclin A2, C-Myc and p15 INK4b , [8][9][10][11] indicating a central role for this family of transcription factors in cellular proliferation and tumorigenesis. Indeed, different NFAT family members have been related to tumor-associated processes, such as growth factor independency, apoptosis, angiogenesis, and invasiveness.…”

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

“…NFAT1, NFAT2, NFAT3 and NFAT4 have been first identified as T-cell transcription factors, whereas NFAT5 has been involved in the cellular response to osmotic stress (Macian, 2005;Burg et al, 2007;Mancini and Toker, 2009;Muller and Rao, 2010). It is now well documented that NFAT proteins are also present in non-immune cells and regulate a variety of signaling pathways involved in cell growth and development (Baksh et al, 2002;Chuvpilo et al, 2002;Mancini and Toker, 2009;Muller and Rao, 2010). Importantly, members of the NFAT family, in particular NFAT5, have recently been involved in the migratory capacity of breast cancer cells (Jauliac et al, 2002;Ayers et al, 2004;Yoeli-Lerner et al, 2005;Mancini and Toker, 2009;Fougere et al, 2010;Muller and Rao, 2010).…”