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Nuclear Factor of Activated T Cells in Cancer Development and Treatment Cancer Letters 361 (2015) 174–184 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Mini-review Nuclear factor of activated T cells in cancer development and treatment Jiawei Shou a, Jing Jing b, Jiansheng Xie c, Liangkun You a, Zhao Jing a, Junlin Yao a, Weidong Han a,c,*, Hongming Pan a,c a Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China b Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China c Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China ARTICLE INFO ABSTRACT Article history: Since nuclear factor of activated T cells (NFAT) was first identified as a transcription factor in T cells, various Received 7 January 2015 NFAT isoforms have been discovered and investigated. Accumulating studies have suggested that NFATs Received in revised form 4 March 2015 are involved in many aspects of cancer, including carcinogenesis, cancer cell proliferation, metastasis, Accepted 4 March 2015 drug resistance and tumor microenvironment. Different NFAT isoforms have distinct functions in differ- ent cancers. The exact function of NFAT in cancer or the tumor microenvironment is context dependent. Keywords: In this review, we summarize our current knowledge of NFAT regulation and function in cancer devel- NFAT opment and treatment. NFATs have emerged as a potential target for cancer prevention and therapy. Calcineurin Tumor microenvironment © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY- Metastasis NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Drug resistance Introduction NFAT therapeutics. Insights into NFAT functions will help to elucidate the NFAT signaling axis mechanism and develop cancer therapies. Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor nearly three decades ago. NFAT was original- The NFAT family and regulation ly found in nuclear extracts from activated T cells. Shaw et al. previously reported that NFAT binds to the interleukin-2 (IL-2) pro- There are five NFAT family members, known as NFAT1 (NFATc2/ moter to activate T cells [1]. NFAT was not well studied until the NFATp), NFAT2 (NFATc1/NFATc), NFAT3 (NFATc4), NFAT4 (NFATc3/ development of immunosuppressants such as cyclosporine A (CsA) NFATx) and NFAT5 (tonicity enhancer binding protein) [4,12].NFAT and tacrolimus (FK506), which block calcineurin activity and inhibit proteins contain an amino-terminal transactivation domain (TAD) NFAT nuclear translocation and consequent target gene transcrip- and a carboxy-terminal domain. NFAT1-4 has two additional con- tion [2]. It was later found that NFAT was also expressed in other served domains, the Rel-homology region (RHR) and NFAT homology cells and tissues, including muscle, bone, neurons, viscera and skin region (NHR). RHR is similar to the DNA-binding domain of the Rel [3–6]. Since the first research demonstrating the relationship family (also known as nuclear factor-κB family), and NHR is a reg- between NFAT and cancer cells was published [7], more evidence ulatory domain with the calcineurin-binding site. Thus, the Ca2+/ has emerged to reveal the roles of NFAT in cancer development and calcineurin pathway regulates NFAT1-4. In contrast, NFAT5 can’t be treatment. activated by calcineurin, as it lacks an NHR [13,14] (Fig. 1A). NFAT plays crucial role in regulating cancer initiation and pro- In resting cells, the NHR is heavily phosphorylated at serine resi- gression, such as proliferation, invasion, migration and angiogenesis dues within several conserved serine-rich sequence motifs (SRR-1, [8–10]. In this review, we focus on the connection between NFATs SPxx repeat, and SRR-2), which can be dephosphorylated by several and three hallmarks of cancer: drug resistance, metastasis and the types of stimulation [15]. When dephosphorylated, the nuclear lo- tumor microenvironment [11]. In addition, we also review the func- calization sequence (NLS) within NFAT is exposed, resulting in the tion of NFAT in carcinogenesis, cell proliferation, and the potential protein’s nuclear translocation. In the nucleus, NFAT cooperates with other transcription factors, such as activator protein 1 (AP1, Fos- Jun complexes), GATA4, MEF families and forkhead box P3 (FOXP3), to initiate target gene transcription [16–18]. NHR rephosphorylation * Corresponding author. Tel.: +86 571 86006926; fax: +86 571 86044817. leads to nuclear export signal (NES) exposure and NLS masking, E-mail address: [email protected] (W. Han). leading to NFAT translocation from the nucleus to the cytoplasm http://dx.doi.org/10.1016/j.canlet.2015.03.005 0304-3835/© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). J. Shou et al./Cancer Letters 361 (2015) 174–184 175 Fig. 1. General structure of NFAT and calcineurin. (A) NFAT proteins consist of the Rel-homology region (RHR), the NFAT homology region (NHR) and a C-terminal domain, while NFAT5 doesn’t possess the NHR. The NHR contains an N-terminal transactivation domain (TAD), the calcineurin binding site, the nuclear localization sequence (NLS) and the nuclear export signal (NES). It also harbors several serine-rich motifs including SRR1, SRR2, SP1, SP2 and SP3. The RHR comprises the DNA binding domain and the recognition points with other transcriptional binding partners such as Fos and Jun. (B) The calcineurin protein has two subunits calcineurin A (CnA) and calcineurin B (CnB). CnA contains a phosphatase catalytic domain and a regulatory domain, the latter owns a CnB-binding domain, a calmodulin-binding domain and an auto-inhibitory domain (AID). CnB has a main latch region with four Ca2+-binding EF-hand motifs, which can be recognized by immunosuppressive complexes and competitively binds to CnA. [19]. This reversible phosphorylation controls NFAT nuclear and cy- catalytic subunit A (CnA) and a regulatory subunit B (CnB). The CnA toplasmic shuttling to switch its transcriptional activity. contains a phosphatase catalytic domain, a CnB-binding domain, a NFAT is primarily activated by store-operated calcium entry via calmodulin-binding domain and a carboxy-terminal auto-inhibitory calcium release-activated calcium (CRAC) channels. The CRAC chan- domain (AID) [26,27]. Under resting condition, the AID interacts with nels include the CRAC channel protein 1 (ORAI1) and stromal the calmodulin-binding domain to inhibit its phosphatase activity. interaction molecule 1 (STIM1) in non-excitable cells [20–23]. Phos- In the activated state, increased cytoplasmic Ca2+ concentration assists pholipase Cγ (PLCγ) activation initiates Ca2+ mobilization. Ligand calmodulin in displacing the AID and promotes CnB binding to CnA binding to cell surface receptors, such as immunoreceptors, recep- by activating Ca2+-binding EF-hand motifs in the CnB. These events tor tyrosine kinases and G-protein-coupled receptor (GPCR), induces ultimately lead to calcineurin activation. The activated calcineurin PLC activation and subsequent phosphatidylinositol-4, 5-bisphosphate dephosphorylates multiple phospho-residues in NFAT NHR, leading (PIP2) hydrolysis into diacylglycerol (DAG) and inositol trisphosphate to NFAT cytoplasmic–nuclear trafficking. Thus, calcineurin plays a 2+ (IP3). IP3 binds to the Ca -permeable IP3 receptor (IP3R) on the en- key role in NFAT dephosphorylation [10,28]. doplasmic reticulum (ER) membrane and stimulates Ca2+ release from In addition to promoting nuclear translocation, calcineurin keeps the stores into the cytosol. Subsequently, STIM1 senses the de- NFAT dephosphorylated and constitutively activated in the nucleus. crease in ER Ca2+, which then forms oligomers and moves to the ER– Therefore, calcineurin inhibition could be an effective way to promote plasma membrane junction, where it gates the plasma membrane NFAT nuclear export and cytoplasmic retention. CsA and FK506 calcium channel ORAI1. This STIM1–ORAI1 interaction induces a con- inhibit calcineurin by binding to its CnB domain. Both compounds formational change in ORAI1, resulting in a persistent rise in are widely used as immunosuppressants in the clinic, mainly in organ intracellular Ca2+ concentration. In addition to the STIM–ORAI system, transplantation and dermatology. In addition, there are several en- there are other Ca2+ channels, including voltage-gated Ca2+ and tran- dogenous calcineurin inhibitors such as Down’s syndrome candidate sient receptor potential ion channels, which are also involved in Ca2+ region 1 (DSCR1), calcineurin-binding protein 1 (CABIN1) and influx across the plasma membrane into the cytoplasm [24,25]. The A-kinase anchor protein 79 (AKAP79) [29–31]. Interestingly, DSCR1 increased cytoplasmic Ca2+ leads to activation of the Ca2+ sensor is upregulated in patients with Down’s syndrome, and these pa- calmodulin (CaM) and CaM further activates the phosphatase tients are less predisposed to malignancy [32]. It was later found calcineurin [4,26]. As shown in Fig. 1B, calcineurin consists of a that DSCR1 suppresses tumor growth by inhibiting the calcineurin 176 J. Shou et al./Cancer Letters 361 (2015) 174–184 pathway [33]. Additionally, blocking targets upstream of the Ca2+/ skin cancer [53,54]. Constitutive NFAT2
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