NFAT transcription factors: from cell cycle to tumor development

Abstract

The nuclear factor of activated T cells (NFAT) family of transcription factors has been primarily identified in immune cells; however, these proteins have been recently found to be functionally active in several other non-immune cell types. NFAT proteins are activated upon different stimuli that lead to increased intracellular calcium levels. Regardless of their widely known cytokine gene expression properties, NFATs have been shown to regulate other genes related to cell cycle progression, cell differentiation and apoptosis, revealing a broader role for these proteins in normal cell physiology. Several reports have addressed the participation of NFATs in many aspects of malignant cell transformation and tumorigenic processes. In this review, we will discuss the involvement of the different NFAT family members in the regulation of cell cycling, differentiation and tumor formation, and also its implications on oncogenesis. Better understanding the mechanisms by which NFATs regulate cell cycle and tumor-related events should be relevant for the development of rational anti-cancer therapies.

Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis

“…These data could be explained by the fact that the IL-11 promotor possesses 2 NFAT-binding sites (39) and supporting the notion that regulation of IL-11 is obsolete in NFAT-KO mice. In support of the suggested role of NFATc2 in the development of inflammation-associated colorectal cancer, it was shown that NFAT functions as an important player in the regulation of CD4 þ T-cell proliferation and activation (40). In the present set of experiments, immunohistochemical analyses of colonic cryosections from NFATc2-KO and wild-type control animals did, however, not reveal any significant differences in the number of colon-residing CD4 þ T cells.…”

“…Apoptosis was found to be critically regulated at both the cellular and molecular levels and to take part in every cell type (40). When analyses of the proapoptotic marker caspase-3 were conducted, we observed significantly enhanced numbers of proapoptotic T cells in tumors from NFATc2-KO mice.…”

TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival

“…Binding sites for NFAT proteins are present in the promoter/enhancer regions of several inducible genes, such as CDK4 (39), and some other cyclin genes (A2, E, and B1) (40). In addition, NFAT2, as well as NFAT3 and NFAT4, appears to function as inductors of cellular proliferation (41). This evidence supports the hypothesis that NFAT transcription factors control the expression of cell cycle-related genes and are central regulators of cell cycle progression.…”

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

“…Indeed, different NFAT family members have been related to tumor-associated processes, such as growth factor independency, apoptosis, angiogenesis, and invasiveness. 12,13 Tumor development is driven by a succession of genetic changes that occur through aberrant cell division cycles, gradually converting normal cells into cancer cells. 14 Cell cycle progression is precisely controlled by the activation of specific cyclin-dependent kinases (CDKs) and their partner cyclins.…”