Dataset Information

Modeling cooperative tumor suppression in the p53 target gene network with in vivo genetic screens and multi-omics

ABSTRACT: The tumor suppressor TP53 is the most frequently mutated gene in human cancer. TP53 encodes a transcriptional activator that induces numerous downstream target genes, but those genes critical for tumor suppression remain elusive. To shed light on the downstream target genes important for tumor suppression, we developed a sensitive and unbiased in vivo CRISPR/Cas9 screening platform to comprehensively map key downstream effectors of p53 in tumor suppression, an essential goal for revealing pathways that could be ultimately therapeutically targeted in p53-deficient tumors. These screens consistently revealed Zmat3 and Cdkn1a as the top-scoring tumor suppressors and demonstrated their capacity to cooperate in tumor suppression. To understand the genetic programs and cellular phenotypes regulated by Zmat3 and Cdkn1a, we used shotgun proteomics to assess differences in protein expression between wild-type, Zmat3 KO, Zmat3 + Cdkn1a KO, and p53 KO E1A;HrasG12V murine embryonic fibroblasts. Functional annotation revealed that various cellular programs including cell division, extracellular signaling and signal transduction, viral response, and ribosome biogenesis become dysregulated in cell lines with alterations to the p53 pathway compared to the wild-type cell lines. These data suggest cellular processes and signaling pathways that provide clues to understanding p53-mediated tumor suppression and for the development of treatments for p53 deficient tumors.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Embryonic Fibroblast

DISEASE(S): Disease Free

SUBMITTER: Janos Demeter

LAB HEAD: Peter K Jackson

PROVIDER: PXD047240 | Pride | 2026-07-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	220829_MS178_MEF_sgACOCB-1_Slot1-32_1_12885.d.zip	Other
	220829_MS178_MEF_sgACOCB-1_Slot1-32_1_12885.mzid.gz	Mzid
	220829_MS178_MEF_sgACOCB-1_Slot1-32_1_12885_uncalibrated.mgf	Mgf
	220829_MS178_MEF_sgACOCB-2_Slot1-33_1_12886.d.zip	Other
	220829_MS178_MEF_sgACOCB-2_Slot1-33_1_12886.mzid.gz	Mzid

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Publications

Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network.

Boutelle Anthony M AM Mabene Aicha R AR Yao David D Xu Haiqing H Wang Mengxiong M Tang Yuning J YJ Lopez Steven S SS Sinha Sauradeep S Demeter Janos J Cheng Ran R Benard Brooks A BA Valente Liz J LJ Drainas Alexandros P AP Fischer Martin M Majeti Ravindra R Petrov Dmitri A DA Jackson Peter K PK Yang Fan F Winslow Monte M MM Bassik Michael C MC Attardi Laura D LD

bioRxiv : the preprint server for biology 20240918

<i>TP53</i> , the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene <i>Zmat3</i> as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppress ...[more]

PMID: 39345444

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