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Phosphoproteomic study looking at the effect of a novel PI3Kα modulator on PI3Kα-WT and PI3Kα-KO mouse embryonic fibroblastsPhosphoproteomic study looking at the effect of a novel PI3Kα modulator on PI3Kα-WT and PI3Kα-KO mouse embryonic fibroblastsPhosphoproteomic study looking at the effect of a novel PI3Kα modulator on PI3Kα-WT and PI3Kα-KO mouse embryonic fibroblasts

ABSTRACT: This project looks at the effect a chemical modulator targeting PI3Kα has on the phosphoproteome of PI3Kα-WT and PI3Kα-KO MEFs. PI3K signalling is a critical regulator of numerous cellular processes such as proliferation, apoptosis, migration, invasion, metabolism, cell growth and autophagy. The PI3K pathway is frequently hyperactivated in cancer, commonly due to activating mutations or via loss of the lipid phosphatases that negatively regulate the pathway. We have recently identified a new small molecule modulator of the PI3K pathway and have used an unbiased phosphoproteomics approach to examine the impact of this compound on signalling pathways in cells that are wild-type and knockout for PI3K. Immortalised mouse embryonic fibroblasts (MEFs) isolated from PI3Kα-WT and PI3Kα-KO embryos were treated with and without the modulator (5 µM), exploring early (15 min) and late (4 h) time points. Insulin is a well-characterised activator of PI3K. Therefore, PI3Kα-WT MEFs were also treated with insulin (100 nM) as a positive control to compare with the PI3K modulator.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Silvia Surinova

LAB HEAD: Silvia Surinova

PROVIDER: PXD027993 | Pride | 2023-03-06

REPOSITORIES: Pride

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Publications

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Gong Grace Q GQ Bilanges Benoit B Allsop Ben B Masson Glenn R GR Roberton Victoria V Askwith Trevor T Oxenford Sally S Madsen Ralitsa R RR Conduit Sarah E SE Bellini Dom D Fitzek Martina M Collier Matt M Najam Osman O He Zhenhe Z Wahab Ben B McLaughlin Stephen H SH Chan A W Edith AWE Feierberg Isabella I Madin Andrew A Morelli Daniele D Bhamra Amandeep A Vinciauskaite Vanesa V Anderson Karen E KE Surinova Silvia S Pinotsis Nikos N Lopez-Guadamillas Elena E Wilcox Matthew M Hooper Alice A Patel Chandni C Whitehead Maria A MA Bunney Tom D TD Stephens Len R LR Hawkins Phillip T PT Katan Matilda M Yellon Derek M DM Davidson Sean M SM Smith David M DM Phillips James B JB Angell Richard R Williams Roger L RL Vanhaesebroeck Bart B

Nature 20230524 7963

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development<sup>1-5</sup>. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial eff ...[more]

PMID: 37225977

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Project description:DNA polymerase zeta (Polz) plays a key role in translesion DNA synthesis. Inactivation of the gene encoding its catalytic subunit (Rev3L) leads to embryonic lethality and abrogates cell proliferation in primary fibroblasts highlighting an essential role of Polz in mammalian cells. However, its biological function remains poorly understood. Here, we examined if the absence of Rev3L may impact on transcriptional program by performing microarray-based transcriptome profiling from Rev3L+/+ and Rev3L-/- MEFs. For this study, we used mouse embryonic fibroblasts (MEF) that are derived from mice harboring one allele with essential exons flanked by loxP sites, and either one inactivated allele of Rev3L (Rev3L−/lox) or, one wild type allele (Rev3L+/lox). Upon introduction of an adenovirus expressing Cre, floxed copy of Rev3L was deleted thus generating Rev3L−/Δ cells, and cell lines were SV40 Tag-immortalized (Lange et al., NAR 2012). We then used Rev3L−/Δ and Rev3L+/lox MEFs (named Rev3L-/- and Rev3L+/+ MEFs, respectively in this study). From two independent cell culture (A and B), total RNAs were extracted from Rev3L+/+ and Rev3L-/- MEFs and processed to determine the transcriptional program in these cell lines. For this study, we used mouse embryonic fibroblasts (MEF) that are derived from mice harboring one allele with essential exons flanked by loxP sites, and either one inactivated allele of Rev3L (Rev3L−/lox) or, one wild type allele (Rev3L+/lox). Upon introduction of an adenovirus expressing Cre, floxed copy of Rev3L was deleted thus generating Rev3L−/Δ cells, and cell lines were SV40 Tag-immortalized (Lange et al., NAR 2012). We then used Rev3L−/Δ and Rev3L+/lox MEFs (named Rev3L-/- and Rev3L+/+ MEFs, respectively in this study). From two independent cell culture (A and B), total RNAs were extracted from Rev3L+/+ and Rev3L-/- MEFs and processed to determine the transcriptional program in these cell lines with Agilent Mouse Genomic array (8x60k) with two replicates in dual color.

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	MSstats.zip	Other
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	regmab2_QEP2_200723_145.raw	Raw
	regmab2_QEP2_200723_149.raw	Raw
	regmab2_QEP2_200723_153.raw	Raw

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Publications

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

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