Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice

Cendrowski, Jaroslaw; Lobo, Víctor J. Sánchez-Arévalo; Sendler, Matthias; Salas, Antonio; Kühn, Jens‐Peter; Molero, Xavier; Fukunaga, Rikiro; Mayerle, Julia; Lerch, Markus M.; Real, Francisco X.

doi:10.1136/gutjnl-2013-306068

Cited by 14 publications

(16 citation statements)

References 41 publications

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“…Myc is required for the replication of prenatal pancreatic (66,67) and adult acinar cells (68). In our study, Myc mRNA was lost rapidly after Ptf1a inactivation, and the MYC-depleted cells were selectively unresponsive to the call for acinar cell regeneration.…”

Section: Discussionmentioning

confidence: 67%

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma. Loss of cellular identity has long been associated with tissue injury and a first step in cancer progression (for examples, see references 1 and 2). Maintenance of a specific cellular phenotype depends on the continued transcription of cell-type-specific genes, largely through open chromatin architecture (3, 4) maintained by a small group of lineage-restricted DNA-binding transcription factors (TFs) (5, 6) that establish a unique transcriptional regulatory network (7). Many physiologic or pathophysiologic perturbations can affect the differentiated state of a cell quantitatively, but fewer affect the state of differentiation qualitatively. Qualitative changes involve the acquisition of characteristics of another cell type (or types), often defined by one or a few cell-specific markers, in addition to the diminution of the original phenotype. Despite progress with cellular reprogramming (for example, see reference 8), the molecular and genetic mechanisms that maintain cellular identity within the context of adult organs remain incompletely understood. In this report, we show that inactivation of the transcriptional regulatory gene Ptf1a in adult pancreatic acinar cells has pleiotropic effects on gene expression that cause quantitative and multigene qualitative changes of acinar differentiation.The acinar cell of the pancreas has been an informative model of terminal cellular differentiation (9). Common cellular processes are greatly exaggerated in support of the prodigious synthesis, processing, storage, and exocytosis of secretory proteins. The pancreatic acinar cell has the most ribosomes (10) and the highest rate of protein synthesis (11) of any mammalian somatic cell; it synthesizes, stores, and secretes its weight in protein daily. Specialized cellular functions ...

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Section: Discussionmentioning

confidence: 67%

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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“…The 3’ UTR sequences have also been found to modulate the rate of mRNA transcription, mRNA stability and pre-recruitment of the signal recognition particle to the ribosome for secreted proteins [51–53]. Alterations in the rate of secretion could also occur as a result of changes in the activity of the eIF4E kinase, MNK1 [54]. Nevertheless, the rate of secretion is unlikely to be involved in the elevated cytoplasmic expression of CXCL8 -5’+3’(-Sec) protein observed in HL-60 Mac relative to A549 EC (Fig 2G).…”

Section: Discussionmentioning

confidence: 99%

Novel AU-rich proximal UTR sequences (APS) enhance CXCL8 synthesis upon the induction of rpS6 phosphorylation

Ang

Koean

et al. 2019

PLoS Genet

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The role of ribosomal protein S6 (rpS6) phosphorylation in mRNA translation remains poorly understood. Here, we reveal a potential role in modulating the translation rate of chemokine (C-X-C motif) ligand 8 ( CXCL8 or Interleukin 8, IL8 ). We observed that more CXCL8 protein was being secreted from less CXCL8 mRNA in primary macrophages and macrophage-like HL-60 cells relative to other cell types. This correlated with an increase in CXCL8 polyribosome association, suggesting an increase in the rate of CXCL8 translation in macrophages. The cell type-specific expression levels were replicated by a CXCL8- UTR-reporter (Nanoluc reporter flanked by the 5’ and 3’ UTR of CXCL8 ). Mutations of the CXCL8 -UTR-reporter revealed that cell type-specific expression required: 1) a 3’ UTR of at least three hundred bases; and 2) an AU base content that exceeds fifty percent in the first hundred bases of the 3’ UTR immediately after the stop codon, which we dub AU-rich proximal UTR sequences (APS). The 5’ UTR of CXCL8 enhanced expression at the protein level and conferred cell type-specific expression when paired with a 3’ UTR. A search for other APS-positive mRNAs uncovered TNF alpha induced protein 6 ( TNFAIP6 ), another mRNA that was translationally upregulated in macrophages. The elevated translation of APS-positive mRNAs in macrophages coincided with elevated rpS6 S235/236 phosphorylation. Both were attenuated by the ERK1/2 signaling inhibitors, U0126 and AZD6244. In A549 cells, rpS6 S235/236 phosphorylation was induced by TAK1, Akt or PKA signaling. This enhanced the translation of the CXCL8 -UTR-reporters. Thus, we propose that the induction of rpS6 S235/236 phosphorylation enhances the translation of mRNAs that contain APS motifs, such as CXCL8 and TNFAIP6 . This may contribute to the role of macrophages as the primary producer of CXCL8, a cytokine that is essential for immune cell recruitment and activation.

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“…Acinar cells were isolated by collagenase digestion and maintained at 37°C in Dulbecco´s modified Eagle medium containing 2% bovine serum albumin and 10 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid as described earlier 26 . Acini were treated either with caerulein (100 pM) or with saline for 24 h prior to RNA and protein isolation.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas

Cobo

Martinelli

Flández

et al. 2018

Nature

113

116

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Summary Chronic inflammation increases the risk of several cancer types. The current notion is that the control of inflammatory responses relies on transcriptional networks distinct from those involved in cell differentiation 1–3. The orphan nuclear receptor NR5A2 participates in a wide variety of processes including cholesterol and glucose metabolism in the liver, resolution of ER stress, intestinal glucocorticoid production, pancreatic development, and acinar differentiation 4–8. Single nucleotide polymorphisms (SNPs) in the vicinity of NR5A2 have been associated with the risk of pancreatic adenocarcinoma (PDAC) through genome wide association studies 9,10. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression 11. Through global transcriptomic analysis, we describe here an epithelial cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2+/− mice that is reminiscent of early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2+/− mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from differentiation-specific to inflammatory genes thereby promoting AP-1-dependent gene transcription. Pancreatic deletion of c-Jun rescues the pre-inflammatory phenotype, Nr5a2 binding to inflammatory gene promoters, and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the same transcriptional networks involved in differentiation-specific functions suppress inflammatory programmes. These networks can be subverted to foster inflammation upon genetic or environmental constraints.

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Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice

Cited by 14 publications

References 41 publications

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Novel AU-rich proximal UTR sequences (APS) enhance CXCL8 synthesis upon the induction of rpS6 phosphorylation

Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas

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