Dataset Information

Human zinc binding cysteine proteome

ABSTRACT: Zinc is an essential micronutrient that regulates a wide range of physiological processes, principally through Zn2+ binding to protein cysteine residues. Despite being critical for modulation of protein function, for the vast majority of the human proteome the cysteine sites subject to Zn2+ binding remain undefined. Here we develop ZnCPT, a deep and quantitative mapping of the zinc binding cysteine proteome. We define 6173 zinc binding protein cysteines, uncovering protein families across major domains of biology that are subject to either constitutive or inducible zinc binding. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc binding, and nominate malignancies sensitive to zinc-induced cytotoxicity. In doing so, we discover a mechanism of zinc regulation over Glutathione Reductase (GSR) that drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation of protein function.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Hct-116 Cell, Prostate Epithelium Cell

SUBMITTER: Nils Burger

LAB HEAD: Edward Chouchani

PROVIDER: PXD057034 | Pride | 2025-01-03

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	2021-11-24-REVUniprot_HUMAN_UP000005640_CanoniIso_sptr_contam_sorted_Canonical1st.fasta	Fasta
	HCT116_PlexA_Run1_S3896.raw	Raw
	HCT116_PlexA_Run1_S3897.raw	Raw
	HCT116_PlexA_Run1_S3898.raw	Raw
	HCT116_PlexA_Run1_S3899.raw	Raw

Items per page:

1 - 5 of 128

Similar Datasets

Project description:Key histological and growth progression characteristics of human prostate cancer are phenocopied in mouse models that have been subjected to androgen level depletion and engineered for hemizygosity of candidate prostate cancer tumor suppressor genes Nkx3.1 and Pten. To characterize their relative transcriptomes and identify a genomic basis for their relevance to human prostate cancers, we compared mouse prostate tumors expression profiles to those from a panel of human prostate cancer isolates and to normal and benign prostates. Human prostate cancers and mouse prostate tumor models both exhibit the activation of genes associated with growth, cell cycle control, and inhibition of differentiation (CDKN2A, CDKN2B, CDKN2C, CEBPB, CEBPG, CSF1, CTSS, DMBT1, EGFR, PLCG2, PXN, SPP1, TNFSF9), and conversely, diminished expression of genes associated with normal prostate differentiation and function. All tumors also exhibit dysregulated expression of genes associated with inflammation, the disruption of prostate-associated ER stress pathways, as well as with oxidative stress, energy metabolism, cell adhesion, and stress response. Immunoinflammatory and altered cell adhesion process-associated genes exhibited prominent expression in early stage tumors. In contrast, metastatic human prostate cancer samples eliminated the expression of most immunoinflammatory-associated transcripts. Cross-species comparisons of molecular programs that are shared or distinguishing of Nkx3.1; Pten mutant mouse models and human adenocarcinomas clearly delineate core tumorigenesis programs associated with cell cycle activation and loss of differentiation. Compared to locally spreading mouse and human tumors, metastatic prostate cancer exhibits greatly reduced expression of immunoinflammatory and adhesion genes, implying that immuno-inflammatory activation may enable first stages of tumorogenesis, but suppress metastasis. These results provide a novel framework to identify stage-specific biomarkers and candidate targets for combinatorial therapeutics. The complex role of inflammation suggests a need for additional caution in countering metastasis. Keywords: tumor stage 26 Affymetrix MOE430A microarrays

Project description:Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging, hence sampling circulating tumor cells (CTCs) may reveal drug resistance mechanisms. We established single cell RNA-sequencing profiles of 77 intact CTCs isolated from 13 patients (mean 6 CTCs/patient) using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing on AR inhibitor, compared with untreated cases indicates activation of noncanonical Wnt signaling (P=0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, while its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure. A total of 221 single candidate prostate CTCs were isolated from 18 patients with metastatic prostate cancer and 4 patients with localized prostate cancer. Of these, 133 cells (60%) had RNA of sufficient quality for amplification and next generation RNA sequencing, and 122 (55%) had >100,000 uniquely aligned sequencing reads. In addition to candidate CTCs, we also obtained comprehensive transcriptomes for 12 bulk primary prostate cancers (macrodissected for >70% tumor content), 30 single cells derived from four different prostate cancer cell lines, and 5 patient-derived leukocyte controls. The leukocytes were readily distinguished by their expression of hematopoietic lineage markers and served to exclude any CTCs with potentially contaminating signals. Strict expression thresholds were used to define lineage-confirmed CTCs, scored by prostate lineage-specific genes (PSA, PSMA, AMACR, AR) and standard epithelial markers (KRT7, KRT8, KRT18, KRT19, EpCAM). 28 cells were excluded given the presence of leukocyte transcripts suggestive of cellular contamination or misidentification during selection, and 17 cells were excluded given low expression of both prostate lineage-specific genes and 5 standard epithelial markers. The remaining 77 cells, defined as lineage-confirmed CTCs, displayed expression of either prostate lineage-specific or epithelial genes, and low expression of leukocyte-specific genes, consistent with their tumor of origin.

Dataset Information

Human zinc binding cysteine proteome

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets