Dataset Information

Mass spectrometry (LC-MS) of survivin binding proteins immunoprecipitated from human THP1 cells

ABSTRACT: The oncoprotein survivin, coded by BIRC5 gene has been shown to bind to chromatin. Chromatin immunoprecipitation of stimulated CD4+ T cells with survivin has been published (GSE190354). The role of survivin in transcriptional regulation acting in synergy with transcription factor complexes has been proposed (ErlandssonM, iScience 2022; Jensen M, iScience 2023). To further characterise survivin function as a transcription factor, this IP-MS study was performed. Human monocyte leukemia cell line (THP-1) was chosen due to it’s high expression level of survivin.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Cell Culture

SUBMITTER: Malin Erlandsson

LAB HEAD: Maria I Bokarewa

PROVIDER: PXD049683 | Pride | 2025-05-06

REPOSITORIES: Pride

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			Action	DRS
	210128_QExHF_AR_MS745_01.raw	Raw
	210128_QExHF_AR_MS745_02.raw	Raw
	210128_QExHF_AR_MS745_03.raw	Raw
	210128_QExHF_AR_MS745_04.raw	Raw
	210128_QExHF_AR_MS745_05.raw	Raw

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Publications

Bivalent chromatin accommodates survivin and BRG1/SWI complex to activate DNA damage response in CD4<sup>+</sup> cells.

Chandrasekaran Venkataragavan V Andersson Karin M E KME Erlandsson Malin M Li Shuxiang S Olsson Torbjörn Nur TN Garcia-Bonete Maria-Jose MJ Malmhäll-Bah Eric E Johansson Pegah P Katona Gergely G Bokarewa Maria I MI

Cell communication and signaling : CCS 20240911 1

<h4>Background</h4>Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4<sup>+</sup> cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4<sup>+</sup> cells in ...[more]

PMID: 39261837

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Project description:The growth and spread of tumors involve intricate interactions with the surrounding tissue microenvironment. As a tumor develops, it faces various stresses from its microenvironment, including hypoxia, nutrient deficiency, and acidosis. In response to these challenges, cancer cells can hijack existing cytoprotective mechanisms, such as the Unfolded Protein Response (UPR). The UPR activates signaling pathways at the translational and later transcriptional levels to alleviate cellular stress and prevent cell death. However, under unresolved or chronic endoplasmic reticulum (ER) stress, the UPR may paradoxically promote cell death. The precise mechanisms through which the UPR influences cellular fate during ER stress remain poorly understood. To address this knowledge gap, we employed a functional CRISPR-based genetic knockout screen to identify novel regulators of the UPR. 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Using a lentiviral genome-wide CRISPR-Cas9 knockout library, we identified over-represented sgRNAs (associated with pro-apoptotic genes) and underrepresented sgRNAs (associated with pro-survival genes) following ER stress induced by Thapsigargin and Tunicamycin. One of the top candidates identified was Survivin/BIRC5, a protein with anti-apoptotic and cell cycle regulatory activities and which is overexpressed in tumor cells compared to healthy tissues. Functional studies revealed that genetic or pharmacological inhibition of Survivin expression enhanced ER stress-induced apoptosis, but not apoptosis in response to other forms of stress. These findings were validated in multiple cancer cell lines, ruling out off-target effects. Mechanistically, ER stress led to PERK-dependent downregulation of Survivin, and overexpression of Survivin blocked Thapsigargin-induced apoptosis. In vivo xenograft models showed that combining Survivin ablation with PERK inhibition significantly delayed tumor growth and improved overall survival. Through a combination of bioinformatics analysis and loss-of-function studies, we identified the transcription factor KLF4 as a mediator of PERK-dependent effects on Survivin repression. Notably, CRISPR-mediated KLF4 knockout successfully rescued Survivin levels post-ER stress. Additionally, an analysis of TCGA data across various tumor types provided supporting evidence of a negative correlation between KLF4 and Survivin expression. In summary, this study unveils a novel regulatory axis, PERK-KLF4-Survivin, as a key determinant of cell fate in the cellular responses to ER stress. Targeting Survivin in conjunction with PERK inhibition showed promising antitumor effects in vivo. The growth and spread of tumors involve intricate interactions with the surrounding tissue microenvironment. 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