Dataset Information

Proteomic analysis of a precision knock-out Glycogen Synthase Kinase 3B model identifies new roles for GSK3B in colorectal cancer

ABSTRACT: Glycogen-specific kinase (GSK3β) is an integral regulator of the Wnt signalling pathway as well as many other diverse signalling pathways and processes. Dys-regulation of GSK3β is implicated in many different pathologies, including neurodegenerative disorders as well as many different tumour types. An important GSK3β mechanism of action is phosphorylation of substrates with consequent inhibition or degradation. In the context of tumour development, GSK3β has been shown to play both oncogenic and tumour suppressor roles, depending upon tissue, signalling environment or disease progression. Although multiple substrates of the GSK3β kinase have been identified, the wider protein networks within which protein-protein interaction networks and complexes within which GSK3β participates are not well known, and the consequences of these interactions not well understood. In this study LC-MS/MS expression analysis of knock-out GSK3β colorectal cancer cells is used as well as to understand the consequences on these interaction partners of GSK3β deletion from the system.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Rob Ewing

LAB HEAD: Rob Ewing

PROVIDER: PXD014919 | Pride | 2021-10-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	KOGSK_Rep1_001.raw.zip	Raw
	KOGSK_Rep1_001_Merged_Spectrum_IA_final_fragment.csv	Csv
	KOGSK_Rep1_002.raw.zip	Raw
	KOGSK_Rep1_003.raw.zip	Raw
	KOGSK_Rep1_004.raw.zip	Raw

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Project description:Similar to resting mature B cells, where the B-cell antigen receptor (BCR) is essential for cellular survival, surface BCR expression is conserved in most mature B cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signaling is required for tumour cell survival. Consequently, the BCR signaling machinery has become a new target in the therapy of B cell malignancies. Here, we studied the effects of BCR ablation on MYC-driven mouse B cell lymphomas and compared them to observations in human Burkitt lymphoma. Whereas BCR ablation did not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappeared in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This required neither cellular contact, nor factors released by BCR+ tumour cells. Instead, BCR loss induced the rewiring of central carbon metabolism increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuated GSK3β activity to support MYC-controlled gene expression. BCR- tumour cells exhibited increased GSK3β activity and were rescued from their competitive growth disadvantage by GSK3β. BCR-negative lymphoma variants that restored competitive fitness, normalized GSK3β following constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate Ig-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR-less tumour cells. In this dataset, we included the expression data obtained from BCR-positive (BCR+) and BCR-negative (BCR-) lymphoma cells co-cultured for 4 days in presence or absence of GSK3b inhibitor, CHIR99021. These data were used to obtain genes that are regulated by the BCR through GSK3b inhibition.

Project description:Similar to resting mature B cells, where the B-cell antigen receptor (BCR) is essential for cellular survival, surface BCR expression is conserved in most mature B cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signaling is required for tumour cell survival. Consequently, the BCR signaling machinery has become a new target in the therapy of B cell malignancies. Here, we studied the effects of BCR ablation on MYC-driven mouse B cell lymphomas and compared them to observations in human Burkitt lymphoma. Whereas BCR ablation did not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappeared in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This required neither cellular contact, nor factors released by BCR+ tumour cells. Instead, BCR loss induced the rewiring of central carbon metabolism increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuated GSK3β activity to support MYC-controlled gene expression. BCR- tumour cells exhibited increased GSK3β activity and were rescued from their competitive growth disadvantage by GSK3β. BCR-negative lymphoma variants that restored competitive fitness, normalized GSK3β following constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate Ig-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR-less tumour cells. In this dataset, we included the expression data obtained from BCR-positive (BCR+), BCR-negative (BCR-) and BCR-independent lymphoma cells co-cultured for four days in presence or absence of GSK3b inhibitor, CHIR99021. This data was used to a) identify genes regulated by the BCR through GSK3b inhibition, and b) identify genes that confers BCR-independency to lymphoma variants resistant to BCR loss.

Dataset Information

Proteomic analysis of a precision knock-out Glycogen Synthase Kinase 3B model identifies new roles for GSK3B in colorectal cancer

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