Allelic effects onKLHL17expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33 DOI Creative Commons
Katelyn E. Connelly, Katherine Hullin,

Ehssan Abdolalizadeh

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 16, 2024

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map functionally characterize a risk signal at 1p36.33 (tagged by rs13303010) identified through genome wide association study (GWAS). One fine-mapped SNPs, rs13303160 (r 2 =0.93 1000G EUR samples, OR=1.23, P value=2.74×10 −9 ) demonstrated allele-preferential gene regulatory activity vitro binding JunB JunD vivo . Expression Quantitative Trait Locus (eQTL) analysis KLHL17 as likely target underlying signal. Proteomic member Cullin-E3 ubiquitin ligase complex PDAC-derived cells. In silico differential expression GTExv8 pancreas data suggested an between lower (risk associated) pro-inflammatory pathways. We hypothesize that may mitigate inflammation recruiting proteins for ubiquitination degradation thereby influencing

Язык: Английский

Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation DOI Creative Commons

Jimin Hu,

Duc T. Huynh,

Denise E. Dunn

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

The 42-member Kelch-like (KLHL) protein family are adaptors for ubiquitin E3 ligase complexes, governing the stability of a wide range substrates. KLHL proteins critical maintaining proteostasis in variety tissues and mutated human diseases, including cancer, neurodegeneration, familial hyperkalemic hypertension. However, regulation remains incompletely understood. Previously, we reported that two members, KEAP1 gigaxonin, regulated by O-linked β- N -acetylglucosamine (O-GlcNAc), an intracellular form glycosylation. Interestingly, some ubiquitination targets gigaxonin themselves also O-GlcNAcylated, suggesting multi-level control this post-translational modification may influence many pathways. To test hypothesis, examined KLHL3, which ubiquitinates with-no-lysine (WNK) kinases to modulate downstream ion channel activity. Our biochemical glycoproteomic data demonstrate KLHL3 all four WNK (WNK1-4) O-GlcNAcylated. Moreover, our results suggest O-GlcNAcylation affects WNK4 function both osmolarity ferroptosis, with potential implications ranging from blood pressure neuronal health survival. This work demonstrates functional KLHL3/WNK axis supports broader model O-GlcNAc serving as general regulator signaling proteostasis.

Язык: Английский

Процитировано

0
The Dual Nature of KLHL Proteins: From Cellular Regulators to Disease Drivers DOI Creative Commons

Verdiana Di Giulio,

Angelo Canciello,

Erminia Carletti

и другие.

European Journal of Cell Biology, Год журнала: 2025, Номер 104(2), С. 151483 - 151483

Опубликована: Март 14, 2025

Язык: Английский

Процитировано

0
The tumor suppressor LZTR1: Its expression, purification and characterization DOI

Yifang Sun,

Yuxuan Jiang, Meng Zhang

и другие.

Protein Expression and Purification, Год журнала: 2025, Номер unknown, С. 106716 - 106716

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33 DOI Creative Commons
Katelyn E. Connelly, Katherine Hullin,

Ehssan Abdolalizadeh

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 30, 2025

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map functionally characterize a risk signal at chr1p36.33 (tagged by rs13303010) identified through genome wide association study (GWAS). One fine-mapped SNPs, rs13303160 (OR = 1.23 (95% CI 1.15-1.32), P-value 2.74×10-9, LD r2 0.93 with rs13303010 1000 G EUR samples) demonstrated allele-preferential gene regulatory activity vitro binding JunB JunD vivo. Expression Quantitative Trait Locus (eQTL) analysis KLHL17 as likely target underlying signal. Proteomic member Cullin-E3 ubiquitin ligase complex vimentin nestin candidate substrates for degradation PDAC-derived cells. In silico differential expression high low expressing GTEx pancreas samples suggested an between lower levels (risk associated) pro-inflammatory pathways. We hypothesize that may mitigate cell injury inflammation recruiting ubiquitination thereby influencing

Язык: Английский

Процитировано

0
Zebrafish Kelch-like protein-4 is required for vasculogenesis and hematopoiesis DOI
Kaitlin Ferrari,

Suman Gurung,

Luiza N. Loges

и другие.

Developmental Biology, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Allelic effects onKLHL17expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33 DOI Creative Commons
Katelyn E. Connelly, Katherine Hullin,

Ehssan Abdolalizadeh

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 16, 2024

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map functionally characterize a risk signal at 1p36.33 (tagged by rs13303010) identified through genome wide association study (GWAS). One fine-mapped SNPs, rs13303160 (r 2 =0.93 1000G EUR samples, OR=1.23, P value=2.74×10 −9 ) demonstrated allele-preferential gene regulatory activity vitro binding JunB JunD vivo . Expression Quantitative Trait Locus (eQTL) analysis KLHL17 as likely target underlying signal. Proteomic member Cullin-E3 ubiquitin ligase complex PDAC-derived cells. In silico differential expression GTExv8 pancreas data suggested an between lower (risk associated) pro-inflammatory pathways. We hypothesize that may mitigate inflammation recruiting proteins for ubiquitination degradation thereby influencing

Язык: Английский

Процитировано

0