Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis.

The Journal of Clinical Investigation
Tewfik HamidiJuan L Iovanna

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients...Continue Reading

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Citations

Nov 10, 2013·PloS One·David Aguado-LleraJuan L Iovanna
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Jan 1, 2014·Molecular & Cellular Oncology·Daniel GrassoJuan L Iovanna
Nov 20, 2018·Scientific Reports·Patricia Santofimia-CastañoJuan Iovanna

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Datasets Mentioned

BETA
GSE35463

Methods Mentioned

BETA
environmental stress
transfection
transgenic
transfections
chip
fluorescence assay
immunoprecipitation
PCR
Protein Assay
electrophoresis

Software Mentioned

limma
GeneChip Operating
Ingenuity
Affymetrix GCOS
Pathway
Cluster
TreeView
SAS
affylmGUI
AffyQCReport

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