Heliyon
·
2023
·
IF 4
Hang-fei Chen,Zhang-ping Li,Qi Wu,Chun Yu,Jing-Yi Yan,Yong-feng Bai,Sheng-mei Zhu,Mao-xiang Qian,Ming Liu,Li-feng Xu,Zheng Peng,Feng Zhang
Hyperactivation of ribosome biosynthesis (RiBi) is a hallmark of cancer, and targeting ribosome biogenesis has emerged as a potential therapeutic strategy. The depletion of TAF1B , a major component of selectivity factor 1 ( SL1 ), disrupts the pre-initiation complex, preventing RNA polymerase I from binding ribosomal DNA and inhibiting the hyperactivation of RiBi. Here, we investigate the role of TAF1B , in regulating RiBi and proliferation in stomach adenocarcinoma (STAD). We disclosed that the overexpression of TAF1B correlates with poor prognosis in STAD, and found that knocking down TAF1B effectively inhibits STAD cell proliferation and survival in vitro and in vivo. TAF1B knockdown may also induce nucleolar stress, and promote c-MYC degradation in STAD cells. Furthermore, we demonstrate that TAF1B depletion impairs rRNA gene transcription and processing, leading to reduced ribosome biogenesis. Collectively, our findings suggest that TAF1B may serve as a potential therapeutic target for STAD and highlight the importance of RiBi in cancer progression.
研究领域:
癌症生物学
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分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2020
·Vol. 42
·期 7
·1190-1194
·
IF 5.064
Shen Zhu-qing,Wang Juan,Tan Wen-fu,Huang Tao-min
Hedgehog plays an important role in a wide range of physiological and pathological conditions. Paracrine activation of Hedgehog pathway in stromal cells increases the expression of VEGF, which promotes neovascularization in colorectal cancer and ultimately the growth of colorectal cancer. Berberine (BBR) has anticancer activity. In this study we investigated whether BBR inhibited the growth of colon cancer through suppressing the paracrine sonic hedgehog (SHH) signaling in vitro and in vivo. We showed that BBR (1–10 μM) dose-dependently inhibited the secretion and expression of SHH protein in HT-29 and SW480 cells. BBR did not influence the transcription of SHH, but promoted the degradation of SHH mRNA, thus decreased the SHH mRNA expression in the colorectal cancer cells. In nude mice bearing HT-29 xenograft, oral administration of BBR (100 mg · kg − 1 · d −1 ) or a positive control drug GDC-0449 (100 mg · kg −1 · d −1 ) for 4 weeks markedly suppressed the growth of HT-29 tumor with BBR exhibiting a better antitumor efficacy. The tumor growth inhibition caused by BBR or GDC-0449 was comparable to their respective inhibitory effect on the mouse-specific Gli mRNA expression in the tumor. However, BBR (20 μM) did not affect the expression of human transcription factor Gli1 mRNA in HT-29 and SW480 cells. In conclusion, BBR promotes the degradation of SHH mRNA in colorectal cancer cells, interrupting the paracrine Hedgehog signaling pathway activity thus suppresses the colorectal cancer growth. This study reveals a novel molecular mechanism underlying the anticancer action of BBR.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
HUMAN MUTATION
·
2025
·Vol. 2025
·期 1
·7194418
·
IF 3.7
Yang Xu,Jie Gao,Yang An,Chenxi Zou,Guoqing Ding,Guohua Yang
Background: Birt–Hogg–Dubé syndrome (BHD) was an autosomal dominant disorder caused by a mutation in the folliculin ( FLCN ) gene and characterized by benign cutaneous fibrofolliculomas in the head and neck, pulmonary cysts, spontaneous pneumothorax, and combined renal tumors. Methods: This study reported a familial case presenting multiple pulmonary bullae, recurrent spontaneous pneumothorax, diffuse cystic lesions in both lungs, and renal cysts. To further clarify the diagnosis, next-generation sequencing (NGS) was performed in conjunction with the clinical diagnostic criteria for Birt–Hogg–Dubé. The eukaryotic recombinant expression vectors of pEGFP-C1- FLCN and knock-in FLCN mutation by CRISPR/Cas9 were conducted in 293 T and BEAS-2B cell lines. The mRNA and protein expression of the FLCN mutation were verified by fluorescence quantitative PCR and Western blot assay. Nonsense-mediated mRNA decay (NMD) assays and immunohistochemical assays were conducted to elucidate the pathogenicity of the mutation and explore potential mechanisms. Results: A unique, novel, unspecified significance FLCN mutation NM_144997.7: c.21_22del (p. Cys8 Profs ∗ 28) in Exon 4 was detected in both patients. The results demonstrated that the newly identified FLCN frameshift mutation significantly decreased FLCN mRNA and protein expression. The NMD complex recognized and degraded mRNAs containing a premature termination codon (PTC) in the open reading frame of the FLCN frameshift mutation, resulting in haploinsufficiency and ultimately contributing to the manifestation of BHD. Protein expression on the AMP-activated protein kinase (AMPK), Wnt/ β -catenin, and mammalian target of rapamycin (mTOR) signaling pathways by immunohistochemistry indicated that FLCN frameshift mutations were responsible for BHD through the activation of AMPK, Wnt/ β -catenin, and mTOR signaling pathways. Conclusion: The study demonstrated that a novel FLCN frameshift mutation was responsible for the pathogenesis of BHD and preliminarily demonstrated that FLCN causes BHD through the AMPK, Wnt/ β -catenin, and mTOR signaling pathways.
研究领域:
医学遗传学
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分子生物学
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临床医学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Zhang Min,Zhang Bin,Liu Chengli,Preußner Marco,Ayachit Megha,Li Weiming,Huang Yafei,Liu Deyi,He Quanwei,Emmerichs Ann-Kathrin,Meinke Stefan,Chen Shu,Wang Lin,Zheng Liduan,Li Qiubai,Huang Qin,Haltenhof Tom,Gao Ruoxi,Qin Xianan,Cheng Aifang,Wei Tianzi,Yu Li,Schubert Mario,Gao Xin,Li Mingchang,Heyd Florian
Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes remains incompletely understood. Here, we discover RNA G-quadruplexes (rG4s) as key thermosensors enriched near splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Specifically, rG4s near splice sites of a cold-repressed poison exon in the neuroprotective RBM3 are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Importantly, stabilizing rG4 through increasing intracellular potassium with an FDA-approved potassium channel blocker, mimics the hypothermic effect on alternative splicing, thereby increasing RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia, especially hemorrhagic stroke.
研究领域:
分子生物学
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神经科学
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RNA生物学
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温度生物学
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基因表达调控
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产品关联
DOI
PubMed
高影响因子
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