Dataset Information

Secretory expression of mammalian NOTCH tandem epidermal growth factor-like repeats based on increased O-glycosylation

ABSTRACT: EGF domains of human NOTCH3 were prepared from HEK293T cells.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tetsuya Okajima

PROVIDER: PXD035703 | JPOST Repository | Sat Jul 27 00:00:00 BST 2024

REPOSITORIES: jPOST

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Dataset's files

Source:

			Action	DRS
	220224_%2304_YTC191-A_5uL-(1).msf	Msf
	220224_%2304_YTC191-A_5uL-(1).msfView	Msf
	220224_%2304_YTC191-A_5uL-(1).pdResult	Other
	220224_%2304_YTC191-A_5uL-(1).pdResultView	Other
	220224_%2304_YTC191-A_5uL.raw	Raw

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Publications

Secretory expression of mammalian NOTCH tandem epidermal growth factor-like repeats based on increased O-glycosylation.

Zhang Ailing A Tsukamoto Yohei Y Takeuchi Hideyuki H Nishiwaki Kimitoshi K Tashima Yuko Y Okajima Tetsuya T

Analytical biochemistry 20220905

The Notch pathway represents evolutionarily conserved intercellular signaling essential for cell-to-cell communication during development. Dysregulation of Notch signaling has been implicated in various diseases, and its control represents a potential cancer treatment strategy. Notch signaling is initiated by the interaction of NOTCH receptors with their ligands on neighboring cells. Therefore, the truncated NOTCH ectodomain, composed mainly of tandem repeats of epidermal growth factor-like (EGF ...[more]

PMID: 36067866

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Project description:Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and increased risk for myelodysplasia and leukemia. Deficient DNA repair contributes to the decline in HSC self-renewal capacity during aging and it remains unclear whether extrinsic signals can rejuvenate aged HSCs. Here, we demonstrate that augmentation of non-homologous end-joining (NHEJ) DNA repair in aged HSCs via treatment with epidermal growth factor (EGF) rejuvenates HSC function. Seven day culture of BM CD34-ckit+sca-1+lin- (34-KSL) HSCs from aged C57BL/6 mice with EGF suppressed myeloid skewing and increased production of multipotent CFU-granulocyte, erythroid, monocyte and megakaryocyte (CFU-GEMM) colonies. Aged, EGF-treated HSCs displayed increased donor multilineage engraftment in primary competitively transplanted mice and in secondary mice compared to mice transplanted with aged, control HSCs. Donor cell engraftment within the bone marrow (BM) KSL and SLAM+KSL HSC population was > 2-fold increased in mice transplanted with aged, EGF-treated HSCs. Systemic administration of EGF to aged mice for 6 weeks also increased long term – HSC self-renewal capacity as measured by increased donor bone marrow (BM) competitive repopulation in primary and secondary transplanted mice. Conversely, deletion of EGFR in Scl/Tal1+ hematopoietic cells was associated with increased myeloid skewing and depletion of LT-HSCs in middle aged mice. Mechanistically, EGF treatment decreased DNA damage in aged HSCs through activation of DNA PK-cs, Artemis and NHEJ repair. Inhibition of DNA PK-cs blocked EGF-mediated restoration of multipotent differentiation and suppression of myeloid skewing in aged HSCs, suggesting that the restoration of hematopoietic potential in aged HSCs is dependent on EGF-mediated activation of DNA PK-cs. EGF treatment also converted the transcriptome of aged HSCs from enrichment for genes involved in cell death and survival to genes involved in HSC generation and identity. These data suggest that extrinsic activation of EGFR signaling can restore key functional capacities in aged HSCs.