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WDR68 stimulates cellular proliferation via activating ribosome biogenesis in 293T cells.

ABSTRACT: WDR68, a conserved WD40 repeat-containing protein, interacts with E1A and is involved in the E1A-induced cell proliferation and oncogenic transformation, but the intrinsic molecular mechanisms of this process remain to be elucidated. Here, we demonstrate that WDR68 promotes the proliferation of 293T cells by interacting with a series of ribosome biogenesis-regulating proteins. Gene Set Enrichment Analysis (GSEA) of RNA-seq data also revealed that the ribosome biogenesis-associated gene signatures could be the most significantly enriched in the WDR68 expression groups. In accordance, 293T cells are more sensitive to the ribosome biogenesis inhibitors than 293 cells. Taken together, our results indicated that WDR68 could promote cell proliferation through the activation of ribosome biogenesis in the 293T cell context. This provides new insights into the understanding of the function of WDR68 and the molecular characterisation of 293T tool cells.

SUBMITTER: Wu Z

PROVIDER: S-EPMC11372390 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature

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WDR68 stimulates cellular proliferation via activating ribosome biogenesis in 293T cells.

Wu Zhaoxia Z Xie Lanfeng L Yuan Ping P Chu Yimin Y Peng Haixia H

Neoplasia (New York, N.Y.) 20240726

WDR68, a conserved WD40 repeat-containing protein, interacts with E1A and is involved in the E1A-induced cell proliferation and oncogenic transformation, but the intrinsic molecular mechanisms of this process remain to be elucidated. Here, we demonstrate that WDR68 promotes the proliferation of 293T cells by interacting with a series of ribosome biogenesis-regulating proteins. Gene Set Enrichment Analysis (GSEA) of RNA-seq data also revealed that the ribosome biogenesis-associated gene signature ...[more]

PMID: 39067242

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Project description:Premature termination codons (PTC) cause over 10% of genetic disease cases. Some aminoglycosides that bind to the ribosome decoding center can induce PTC readthrough and restore low levels of full-length functional proteins. However, concomitant inhibition of protein synthesis limits the extent of PTC readthrough that can be achieved by aminoglycosides like G418. Using a cell-based screen, we identified a small molecule, the phenylpyrazoleanilide Y-320, that potently enhances TP53, DMD, and COL17A1 PTC readthrough by G418. Unexpectedly, Y-320 increased cellular protein levels and protein synthesis, measured by SYPRO Ruby protein staining and puromycin labeling, as well as ribosome biogenesis measured using antibodies to rRNA and ribosomal protein S6. Y-320 did not increase the rate of translation elongation and it exerted its effects independently of mTOR signaling. At the single cell level, exposure to Y-320 and G418 increased ribosome content and protein synthesis which correlated strongly with PTC readthrough. As a single agent, Y-320 did not affect translation fidelity measured using a luciferase reporter gene but it enhanced misincorporation by G418. RNA-seq data showed that Y-320 up-regulated the expression of CXC chemokines CXCL10, CXCL8, CXCL2, CXCL11, CXCL3, CXCL1, and CXCL16. Several of these chemokines exert their cellular effects through the receptor CXCR2 and the CXCR2 antagonist SB225002 reduced cellular protein levels and PTC readthrough in cells exposed to Y-320 and G418. These data show that the self-limiting nature of PTC readthrough by G418 can be compensated by Y-320, a potent enhancer of PTC readthrough that increases ribosome biogenesis and protein synthesis. They also support a model whereby increased PTC readthrough is enabled by increased protein synthesis mediated by an autocrine chemokine signaling pathway. The findings also raise the possibility that inflammatory processes affect cellular propensity to readthrough agents and that immunomodulatory drugs like Y-320 might find application in PTC readthrough therapy.

Dataset Information

WDR68 stimulates cellular proliferation via activating ribosome biogenesis in 293T cells.

Publications

WDR68 stimulates cellular proliferation via activating ribosome biogenesis in 293T cells.

Similar Datasets

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