Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

Abstract

Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumor of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.

Endoplasmic reticulum stress related IncRNA signature predicts the prognosis and immune response evaluation of uterine corpus endometrial carcinoma

“…The association of NOD1 and NOD2 with proinflammatory responses induced by IRE1α/TRAF2 signaling provides a novel link between innate immunity and ER stress-induced inflammation ( 30 ). The activation of UPR caused by ER stress may help to correct the increased level of GLP-1/Notch signaling and the associated overproliferation in the germ line of C. elegans ( 31 ). The ss-GSEA results demonstrate a significant relationship between the prediction signatures and dendritic cell activation, immature dendritic cells, immune status of the Treg, and dendritic cell activation.…”

C. elegans Germline as Three Distinct Tumor Models

“…Derlin family proteins: Singh et al demonstrated that reduced CUP-2 and DER-2 function suppresses GLP-1/Notch-mediated germline tumorigenesis [ 22 ]. CUP-2 and DER-2 are Derlin family proteins that function in endoplasmic reticulum (ER)-associated degradation (ERAD).…”

“…They also found that the suppression of GLP-1/Notch-mediated germline tumorigenesis by the cup-2 mutation requires a proper Unfolded Protein Response (UPR) function. Therefore, they suggest that reduced Derlin activity may suppress GLP-1/Notch-mediated tumorigenesis through the activation of ER stress and UPR [ 22 ].…”

C. elegans Germline as Three Distinct Tumor Models

“…Derlin family proteins: Singh et al demonstrated that reduced CUP-2 and DER-2 function suppresses GLP-1/Notch-mediated germline tumorigenesis[21]. CUP-2 and DER-2 are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD).…”

“…CUP-2 and DER-2 are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD). Therefore, they suggest that Derlin activity may be associated with GLP-1/Notch-mediated tumorigenesis[21].  U/T level: Chi et al demonstrated that GLP-1 expression in the distal gonad region is repressed by low Uridine/Thymidine (U/T) levels[22].…”