User talk:Immcarle63/sandbox

Article Evaluation
NFAT Page

Talk Page: WikiProject Molecular and Cell Biology: Ranked Start Class and low importance WikiProject Cell Signaling: start class no other talk/ discussion on this page

need to learn more about transcription factors and how they work but i would like to add more detail about the signal cascade and the specifics of what NFAT does and what its pathways are or other transcription factors it works with I could maybe add history of how it was discovered. This is already a fairly neutral article so I just need to keep adding more information

need more info in the pharmacological target section and breast cancer section all info seems to have citations so far seems like basic facts are there but the article needs to be expanded I would like to add more sections on the relevance of NFAT to perhaps other disorders or outside topics (clinical significance section or other Immcarle63 (talk) 19:34, 14 January 2018 (UTC)Immcarle63

update 2/5: Biggest sections I will be adding are on the relationship between NFAT and inflammation as well as NFAT being a cancer treatment target (adding to the section on NFAT and breast cancer. Sources: Macián, F., López-Rodríguez, C., & Rao, A. (2001). Partners in transcription: NFAT and AP-1. Oncogene, 20(19), 2476–2489. https://doi.org/10.1038/sj.onc.1204386 Medyouf, H., & Ghysdael, J. (2008). The calcineurin/NFAT signaling pathway: a novel therapeutic target in leukemia and solid tumors. Cell Cycle (Georgetown, Tex.), 7(3), 297–303. https://doi.org/10.4161/cc.7.3.5357 Nguyen, T., & Di Giovanni, S. (2008). NFAT signaling in neural development and axon growth. International Journal of Developmental Neuroscience: The Official Journal of the International Society for Developmental Neuroscience, 26(2), 141–145. https://doi.org/10.1016/j.ijdevneu.2007.10.004 Pan, M.-G., Xiong, Y., & Chen, F. (2013). NFAT Gene Family in Inflammation and Cancer. Current Molecular Medicine, 13(4), 543–554. https://doi.org/10.2174/1566524011313040007 Qin, J.-J., Nag, S., Wang, W., Zhou, J., Zhang, W.-D., Wang, H., & Zhang, R. (2014). NFAT as cancer target: mission possible? Biochimica Et Biophysica Acta, 1846(2), 297–311. https://doi.org/10.1016/j.bbcan.2014.07.009 Rao, A., Luo, C., & Hogan, P. G. (1997). Transcription factors of the NFAT family: regulation and function. Annual Review of Immunology, 15, 707–747. https://doi.org/10.1146/annurev.immunol.15.1.707 Immcarle63 (talk) 21:44, 5 February 2018 (UTC)immcarle63

Article Draft
Things to add: picture of NFAT

expand on intro

add to section on inflammation

add to Cancer section with information on lymphoid tissue cancer

NFAT and neural development

maybe put drug target information higher up?

maybe add history of discovery

copied from NFAT page for editing in sandbox

more on AP-1 and NFAT in signaling/binding section Intro:

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. (could add to this to make it a little more detailed Family members The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4, and NFAT5.[1] NFATc1 through NFATc4 are regulated by calcium signaling. Calcium signaling is critical to NFAT activation because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats in the amino termini of NFAT proteins, resulting in a conformational change that exposes a nuclear localization signal, resulting in NFAT nuclear import.

What I'm adding: NFATc1 and NFAT c2 mRNAs are expressed in peripheral lymphoid tissue, while NFATc4 is highly expressed in the thymus. NFATc3 mRNA however, is expressed at low levels in lymphoid tissue, so it may be more preferentially expressed outside the immune system

Signaling and Binding Sites Nuclear import of NFAT proteins is opposed by maintenance kinases in the cytoplasm and export kinases in the nucleus. Export kinases, such as PKA and GSK-3β, must be inactivated for NFAT nuclear retention.

NFAT proteins have weak DNA-binding capacity. Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.[2] This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signaling pathways such as ras-MAPK or PKC. In addition, this signaling integration is involved in tissue-specific gene expression during development. A screen of ncRNA sequences identified in EST sequencing projects[3][4] discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON.[5]

What I'm adding:

The best known classes of binding sites for NFAT are the formation of a cooperative complex with AP-1 or other bZIP proteins and the binding to sites for conventional Rel-family proteins.

NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites, which indicates that higher order, synergistic interactions between the relevant proteins in a cooperative complex is needed for effective transcription.

Clinical significance Inflammation NFAT plays a role in the regulation of inflammation of inflammatory bowel disease (IBD). In the gene that encodes LRRK2 (leucine-rich repeat kinase 2), a susceptibility locus for IBD was found.[6] The kinase LRRK2 is an inhibitor for the NFATc2 variety, so in mice lacking LRRK2, increased activation of NFATc2 was found in macrophages.[6] This led to an increase in the NFAT-dependent cytokines that spark severe colitis attacks.

Breast cancer NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma [7][8] and NFAT3 (NFATc4) is an inhibitor of cell motility.[9] NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast cancer cell invasion [10] and NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.[9]

As a drug target Due to its essential role in the production of the T-cell proliferative cytokine interleukin-2, NFAT signaling is an important pharmacological target for the induction of immunosuppression. CN inhibitors, which prevent the activation of NFAT, including cyclosporine A (CsA) and tacrolimus(FK506), are used in the treatment of rheumatoid arthritis, multiple sclerosis, Crohn's disease, and ulcerative colitis[11] and to prevent the rejection of organ transplants.[12]

What I'm adding: However, there is a toxicity associated with these drugs due to their ability to inhibit CN in non-immune cells, which limits their use in other situations that may call for immunosuppressing drug therapy, including allergy and inflammation. There are other compounds that target NFAT directly, as opposed to the phosphatase activity of calcineurin, that may have broad immunosuppressive effects but lack the toxicity of CsA and FK506. Because individual NFAT proteins exist in specific cell types or affect specific genes, it may be possible to inhibit individual NFAT protein functions for an even more selective immune effect. Immcarle63 (talk) 23:41, 5 February 2018 (UTC)immcarle63