Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.11.2 (prolyl hydroxylase)
 1,814 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intestinal epithelia self-renew constantly and generate differentiated cells such as secretary goblet cells. The intestine goblet cells secrete gel-forming mucins that form mucus to create a barrier of defense. We reported previously that loss of prolyl hydroxylase (PHD) 3 led to disruption of the intestinal epithelial barrier function. However, the underlying mechanism remains elusive. Here, we demonstrate that PHD3 controls the generation of intestine goblet cell. We found that genetic ablation of Phd3 in mice intestine epithelial cells reduced the amount of goblet cells. Mechanistically, PHD3 bounds the E3 ubiquitin ligase HUWE1 and prevented HUWE1 from mediating ubiquitination and degradation of ATOH1, an essential driver for goblet cell differentiation. The prolyl hydroxylase activity-deficient variant PHD3(H196A) also prevented ATOH1 destruction. A genetic intestine epithelial PHD3(H196A)-knockin had no effect on ATOH1 expression or goblet cell amount in mice, suggesting that the PHD3 prolyl hydroxylase activity is dispensable for its ability to control ATOH1 expression and goblet cell generation. In dextran sulfate sodium (DSS)-induced experimental colitis, PHD3-knockout rather than PHD3(H196A)-knockin sensitized the mice to DSS treatment. Our results reveal an additional critical mechanism underlying the regulation of ATOH1 expression and goblet cell generation and highlight that PHD3 plays a role in controlling intestine goblet cell generation in a hydroxylase-independent manner.
 ...
PMID:Prolyl hydroxylase 3 controls the intestine goblet cell generation through stabilizing ATOH1. 3195 16

Maintaining oxygen homeostasis is a most basic cellular process for adapting physiological oxygen variations, and its abnormality typically leads to various disorders in the human body. The key molecules of the oxygen-sensing system include the transcriptional regulator hypoxia-inducible factor (HIF), which controls a wide range of oxygen responsive target genes (eg, EPO and VEGF), certain members of the oxygen/2-oxoglutarate-dependent dioxygenase family, including the HIF proline hydroxylase (PHD, alias EGLN), and an E3 ubiquitin ligase component for HIF destruction called von Hippel-Lindau. In this review, we summarize the physiological role and highlight the pathologic function for each protein of the oxygen-sensing system. A better understanding of their molecular mechanisms of action will help uncover novel therapeutic targets and develop more effective treatment approaches for related human diseases, including cancer.
 ...
PMID:Understanding the Oxygen-Sensing Pathway and Its Therapeutic Implications in Diseases. 3233 95

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel-Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.
 ...
PMID:Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression. 3314 30


<< Previous 1 2 3