14 research outputs found

    Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation

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    Neural precursor cells (NPCs) differentiate into neurons, astrocytes, and oligodendrocytes in response to intrinsic and extrinsic changes. Notch signals maintain undifferentiated NPCs, but the mechanisms underlying the neuronal differentiation are largely unknown. We show that SIRT1, an NAD+-dependent histone deacetylase, modulates neuronal differentiation. SIRT1 was found in the cytoplasm of embryonic and adult NPCs and was transiently localized in the nucleus in response to differentiation stimulus. SIRT1 started to translocate into the nucleus within 10 min after the transfer of NPCs into differentiation conditions, stayed in the nucleus, and then gradually retranslocated to the cytoplasm after several hours. The number of neurospheres that generated Tuj1+ neurons was significantly decreased by pharmacological inhibitors of SIRT1, dominant-negative SIRT1 and SIRT1-siRNA, whereas overexpression of SIRT1, but not that of cytoplasm-localized mutant SIRT1, enhanced neuronal differentiation and decreased Hes1 expression. Expression of SIRT1-siRNA impaired neuronal differentiation and migration of NPCs into the cortical plate in the embryonic brain. Nuclear receptor corepressor (N-CoR), which has been reported to bind SIRT1, promoted neuronal differentiation and synergistically increased the number of Tuj1+ neurons with SIRT1, and both bound the Hes1 promoter region in differentiating NPCs. Hes1 transactivation by Notch1 was inhibited by SIRT1 and/or N-CoR. Our study indicated that SIRT1 is a player of repressing Notch1-Hes1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of NPCs

    Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer

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    Tumor-infiltrating lymphocytes in the tumor microenvironment are important in the treatment of triple-negative breast cancer (TNBC). Cytotoxic T cells produce cytokines and cytotoxic factors, such as perforin and granzyme, which induce apoptosis by damaging target cells. To identify biomarkers of these cells, we investigated granzyme B (GZMB) in the tumor microenvironment as a biomarker of treatment response and prognosis in 230 patients with primary TNBC who underwent surgery without preoperative chemotherapy between January 2004 and December 2014. Programmed cell death ligand 1 (PD-L1) positivity was defined as a composite positive score ≥10 based on the PD-L1 immunostaining of tumor cells and immune cells. GZMB-high was defined as positivity in ≥1% of tumor-infiltrating lymphocytes (TILs). Among the 230 TNBC patients, 117 (50.9%) had CD8-positive infiltrating tumors. In the PD-L1-positive group, a Kaplan–Meier analysis showed that GZMB-high TNBC patients had better recurrence-free survival (RFS) and overall survival (OS) than GZMB-low patients and that OS was significantly longer (RFS: p = 0.0220, OS: p = 0.0254). A multivariate analysis also showed significantly better OS in PD-L1- and GZMB-high patients (hazard ratio: 0.25 (95% IC: 0.07–0.88), p = 0.03). Our findings indicate that GZMB is a useful prognostic biomarker in PD-L1-positive TNBC patients

    Growth and Yield Properties of Near-Isogenic Wheat Lines Carrying Different Photoperiodic Response Genes

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    Near-isogenic lines (NILs), carrying different combinations of Ppd-1 genes in the genetic background of an early-maturity cultivar Abukumawase were grown at two sites for two years to elucidate the effects of photoperiodic response genes on the growth and yield of early-maturity wheat ( Triticum aestivum L.) in central and southwestern Japan. Photoperiod-insensitive genes, Ppd-B1a and Ppd-D1a , accelerated young spike development, and this effect was predominant with Ppd-B1 with no additive effect among them. Ppd-B1a and Ppd-D1a also advanced the jointing stage, heading, and maturity, and the effect of Ppd-B1a on the jointing stage and heading was stronger than that of Ppd-D1a. An additive effect of two genes was detected for heading. Besides, Ppd-B1a and Ppd-D1a reduced culm length and grain weight, although the reduction effect on grain weight was not significant. Meanwhile, the mean temperature from double ridge formation stage to heading was lower in NILs with photoperiod-insensitive genes than in NILs with photoperiod-sensitive gene, and there was a significant correlation between mean temperature from double ridge formation stage to terminal spikelet formation stage and spikelet number per spike as well as between mean temperature from terminal spikelet formation stage to heading and grain number per spikelet. Therefore in a genetic background of extremely early-maturity line of spring type wheat, photoperiod-insensitive genes accelerated wheat growth and reduced spikelet numbers in central and southwestern Japan, and the effect of Ppd-B1a was stronger than that of Ppd-D1a
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