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NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation

Author

Listed:
  • Isidoro Cobo

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Sumit Paliwal

    (Spanish National Cancer Research Centre-CNIO)

  • Cristina Bodas

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Irene Felipe

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Júlia Melià-Alomà

    (Spanish National Cancer Research Centre-CNIO
    Universitat Pompeu Fabra)

  • Ariadna Torres

    (Spanish National Cancer Research Centre-CNIO
    Universitat Pompeu Fabra)

  • Jaime Martínez-Villarreal

    (Spanish National Cancer Research Centre-CNIO)

  • Marina Malumbres

    (The Barcelona Institute of Science and Technology)

  • Fernando García

    (Spanish National Cancer Research Centre-CNIO, ProteoRed-Instituto de Salud Carlos III)

  • Irene Millán

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Natalia Pozo

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Joo-Cheol Park

    (Seoul National University)

  • Ray J. MacDonald

    (University of Texas Southwestern Medical Center)

  • Javier Muñoz

    (Spanish National Cancer Research Centre-CNIO, ProteoRed-Instituto de Salud Carlos III)

  • Raúl Méndez

    (The Barcelona Institute of Science and Technology
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Francisco X. Real

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC
    Universitat Pompeu Fabra)

Abstract

Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.

Suggested Citation

  • Isidoro Cobo & Sumit Paliwal & Cristina Bodas & Irene Felipe & Júlia Melià-Alomà & Ariadna Torres & Jaime Martínez-Villarreal & Marina Malumbres & Fernando García & Irene Millán & Natalia Pozo & Joo-C, 2023. "NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39291-x
    DOI: 10.1038/s41467-023-39291-x
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    References listed on IDEAS

    as
    1. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Isidoro Cobo & Paola Martinelli & Marta Flández & Latifa Bakiri & Mingfeng Zhang & Enrique Carrillo-de-Santa-Pau & Jinping Jia & Víctor J. Sánchez-Arévalo Lobo & Diego Megías & Irene Felipe & Natalia , 2018. "Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas," Nature, Nature, vol. 554(7693), pages 533-537, February.
    3. Kim, Jaehoon & Kim, Sangsin, 2015. "2012년 국회법 개정의 효과 연구 [A Study on the Effect of the 2012 National Assembly Act Amendment]," KDI Research Monographs, Korea Development Institute (KDI), volume 127, number v:2015-03(k):y:2015:p:1-1.
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    1. Huan Zhang & Yan Sun & Zhaokai Wang & Xiaoju Huang & Lu Tang & Ke Jiang & Xin Jin, 2024. "ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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