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The transcription factor NFAT plays key roles in multiple biological activities, such as immune responses, tissue development and malignant transformation. NFAT is dephosphorylated by calcineurin, which is activated by intracellular calcium levels, and translocated into the nucleus, resulting in transcriptional activation. Calcineurin dephosphorylates various target proteins and regulates their functions. However, the regulation of NFAT degradation is largely unknown, and it is unclear whether calcineurin contributes to the stability of NFAT. We investigated the effect of calcineurin inhibition on NFAT protein stability and found that the dephosphorylation of NFAT by calcineurin promotes the NFAT stabilization, whereas calcineurin mutant that is defective in phosphatase activity was unable to stabilize NFAT. Increased intracellular calcium ion concentration, which is essential for calcineurin activation, also induced NFAT stability. In addition, we identified S-phase kinase associated protein 2 (Skp2), an F-box protein of the SCF ubiquitin ligase complex, as a factor mediating degradation of NFAT when calcineurin was depleted. In summary, these findings revealed that the dephosphorylation of NFAT by calcineurin protects NFAT from degradation by Skp2 and promotes its protein stability. [ABSTRACT FROM AUTHOR]

FK506 binding protein 52 (FKBP52) (gene name FKBP4) is a 52 kDa protein that belongs to the FKBP family; it binds to the immunosuppressant FK506 and has proline isomerase activity. In addition to its FK domain‐containing peptidylprolyl isomerase activity, FKBP52 also acts as a cochaperone through the tetratricopeptide repeat domain that mediates binding to heat shock protein 90. Previous studies have reported that FKBP52 is associated with hormone‐dependent, stress‐related, and neurodegenerative diseases, revealing its diverse functions. In particular, the effects of FKBP52 on cancer have attracted considerable attention. FKBP52 promotes the growth of hormone‐dependent cancers by activating steroid hormone receptors. Recent studies have shown that the expression of FKBP52 is increased not only in steroid hormone‐dependent cancer cells but also in colorectal, lung, and liver cancers, revealing its diverse functions that contribute to cancer growth. This review summarizes reports related to hormone‐dependent cancer and cell proliferation in terms of the structure of FKBP52 and its function on interacting molecules. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that mediate repression of target genes by trimethylation of Lys27 in histone 3 (H3K27me3). Given the reported roles of EZH2 in cancer, it is perhaps not surprising that targeting EZH2 in cancer therapy has become a hot research topic. Indeed, different types of EZH2 inhibitors are currently under development and are being evaluated by clinical trials. Recently, Murashima et al. identified NPD13668, a novel EZH2 inhibitor, by using a cell-based high-throughput screening assay. NPD13668 inhibited EZH2 methyltransferase activity, and repressed cell growth in multiple cancer cell lines, indicating a potential role for this compound in cancer treatment. In this review, we will focus on the current knowledge regarding the biological significance of PRC2 and H3K27me, and the recent advances in developing and testing drugs that target PRC2. [ABSTRACT FROM AUTHOR]

DNA damage induces transcriptional repression of E2F1 target genes and a reduction in histone H3‐Thr11 phosphorylation (H3‐pThr11) at E2F1 target gene promoters. Dephosphorylation of H3‐pThr11 is partly mediated by Chk1 kinase and protein phosphatase 1γ (PP1γ) phosphatase. Here, we isolated NIPP1 as a regulator of PP1γ‐mediated H3‐pThr11 by surveying nearly 200 PP1 interactor proteins. We found that NIPP1 inhibits PP1γ‐mediated dephosphorylation of H3‐pThr11 both in vivo and in vitro. By generating NIPP1‐depleted cells, we showed that NIPP1 is required for cell proliferation and the expression of E2F1 target genes. Upon DNA damage, activated protein kinase A (PKA) phosphorylated the NIPP1‐Ser199 residue, adjacent to the PP1 binding motif (RVxF), and triggered the dissociation of NIPP1 from PP1γ, leading to the activation of PP1γ. Furthermore, the inhibition of PKA activity led to the activation of E2F target genes. Statistical analysis confirmed that the expression of NIPP1 was positively correlated with E2F target genes. Taken together, these findings demonstrate that the PP1 regulatory subunit NIPP1 modulates E2F1 target genes by linking PKA and PP1γ during DNA damage. [ABSTRACT FROM AUTHOR]

UHRF1 (Ubiquitin‐like with PHD and ring finger domains 1) regulates DNA methylation and histone modifications and plays a key role in cell proliferation and the DNA damage response. However, the function of UHRF2, a paralog of UHRF1, in the DNA damage response remains largely unknown. Here, we show that UHRF2 is essential for maintaining cell viability after UV irradiation, as well as for the proliferation of cancer cells. UHRF2 was found to physically interact with ATR in a DNA damage‐dependent manner through UHRF2's TTD domain. In addition, phosphorylation of threonine at position 1989, which is required for UV‐induced activation of ATR, was impaired in cells depleted of UHRF2, suggesting that UHRF2 is essential in ATR activation. In conclusion, these results suggest a new regulatory mechanism of ATR activation mediated by UHRF2. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) is highly expressed or abnormally activated in several types of cancers, such as lung and colorectal cancers. Inhibitors that suppress the tyrosine kinase activity of EGFR have been used in the treatment of lung cancer. However, resistance to these inhibitors has become an issue in cancer treatment, and the development of new therapies that inhibit EGFR is desired. We found that calcineurin, a Ca2+/calmodulin-activated serine/threonine phosphatase, is a novel regulator of EGFR. Inhibition of calcineurin by FK506 treatment or calcineurin depletion promoted EGFR degradation in cancer cells. In addition, we found that calcineurin dephosphorylates EGFR at serine (S)1046/1047, which in turn stabilizes EGFR. Furthermore, in human colon cancer cells transplanted into mice, the inhibition of calcineurin by FK506 decreased EGFR expression. These results indicate that calcineurin stabilizes EGFR by dephosphorylating S1046/1047 and promotes tumor growth. These findings suggest that calcineurin may be a new therapeutic target for cancers with high EGFR expression or activation. • Calcineurin depletion reduces EGFR expression and attenuates EGFR signaling. • Calcineurin increases EGFR stability via dephosphorylation at Ser1046/1047. • Inhibiting lysosome function inhibits EGFR degradation in FK506-treated cells. • Calcineurin inhibition suppresses EGFR expression in vivo. [ABSTRACT FROM AUTHOR]