scholarly journals Targeting unfolded protein response in cancer and diabetes

2015 ◽  
Vol 22 (3) ◽  
pp. C1-C4 ◽  
Author(s):  
Souren Mkrtchian
Keyword(s):  
South Carolina ◽  
Unfolded Protein Response ◽  
Signal Transduction Pathway ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Enhancer Binding Protein ◽  
Apoptotic Activity ◽  
The Unfolded Protein Response ◽  
Protein Response

The maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is tightly regulated by the unfolded protein response (UPR), a signal transduction pathway maintaining ER protein folding homeostasis. However, certain ER states are incompatible with cell survival and therefore the UPR may choose to eliminate severely disrupted cells by apoptosis. This is accomplished primarily through the activation of the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP). In the April 2015 issue of Endocrine-Related Cancer, researchers from the universities of South Carolina and Athens (Greece) suggested a novel mechanism of CHOP-mediated apoptosis connected with the suppression of a prominent cell cycle regulator with anti-apoptotic activity, p21. These findings and suggested clinical applications, such as potentiation of cancer chemotherapy and a novel therapeutic approach for type 2 diabetes, are discussed in the context of UPR.

Role of the Unfolded Protein Response Pathway in Regulation of INO1 and in the sec14 Bypass Mechanism in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 162 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Hak J Chang ◽  
Elizabeth W Jones ◽  
Susan A Henry
Keyword(s):  
Unfolded Protein Response ◽  
Genetic Background ◽  
Synthetic Lethality ◽  
Signal Transduction Pathway ◽  
Phospholipid Metabolism ◽  
Wild Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract INO1, encoding inositol 1-phosphate synthase, is the most highly regulated of a class of genes containing the repeated element, UASINO, in their promoters. Transcription of UASINO-containing genes is modulated by the availability of exogenous inositol and by signals generated by alteration of phospholipid metabolism. The unfolded protein response (UPR) pathway also is involved in INO1 expression and the ire1Δ and hac1Δ mutants are inositol auxotrophs. We examined the role of the UPR in transmitting a signal generated in response to inositol deprivation and to alteration of phospholipid biosynthesis created in the sec14ts cki1Δ genetic background. We report that the UPR is required for sustained high-level INO1 expression in wild-type strains, but not for transient derepression in response to inositol deprivation. Moreover, the UPR is not required for expression or regulation of INO1 in response to the change in lipid metabolism that occurs in the sec14ts cki1Δ genetic background. Thus, the UPR signal transduction pathway is not involved directly in transcriptional regulation of INO1 and other UASINO-containing genes. However, we discovered that inactivation of Sec14p leads to activation of the UPR, and that sec14 cki1 strains exhibit defective vacuolar morphology, suggesting that the mechanism by which the cki1Δ mutation suppresses the growth and secretory defect of sec14 does not fully restore wild-type morphology. Finally, synthetic lethality involving sec14 and UPR mutations suggests that the UPR plays an essential role in survival of sec14 cki1 strains.

The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1α

2011 ◽  
Vol 91 (4) ◽  
pp. 1219-1243 ◽  
Author(s):  
Claudio Hetz ◽  
Fabio Martinon ◽  
Diego Rodriguez ◽  
Laurie H. Glimcher
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Signal Transduction Pathway ◽  
Secretory Cells ◽  
Factor X ◽  
Stress Sensor ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

Oestrogen-driven changes in the bovine uterus are associated with activation of the unfolded protein response

2014 ◽  
Author(s):  
Mohammed A Alfattah ◽  
Paul Anthony McGettigan ◽  
John Arthur Browne ◽  
Khalid M Alkhodair ◽  
Katarzyna Pluta ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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