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LncRNA LIMp27 regulates the DNA damage response through p27 in p53-defective cancer cells

ABSTRACT: P53 inactivation occurs in about 50% human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasm-localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at G0/G1 phase. In response to DNA-damage, LIMp27 is upregulated in both wild-type and p53-muant COAD cells, whereas cytoplasmic hnRNPA0 is only increased due to translocation from the nucleus in p53-mutant COAD cells. High LIMp27 expression is associated with poor survival of p53-mutant but not wide-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208711 | GEO | 2022/12/31

REPOSITORIES: GEO

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LncRNA LIMp27 regulates the DNA damage response through p27 in p53-defective cancer cells

Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

| MSV000090292 | MassIVE

C-terminally phosphorylated p27 regulates STAT3 transcriptional activation, inducing gene programs driving mammary duct and cancer stem cell expansion

Project description:While, p27 inhibits cell cycle in normal cells, in most cancers, p27 acquires oncogenic activities when phosphorylated by PI3K-activated kinases at T157 and T198 (p27pTpT). Mechanistically, these oncogenic functions of p27pTpT are poorly understood. Here, we show that p27pTpT promotes cancer stem cell (CSC) expansion through STAT3 both in vitro and in vivo. p27 phosphorylation increased STAT3 recruitment to chromatin to induce CSC self-renewal genes including MYC, the Notch ligand, JAG1, and ANGPTL4. We identify a feed-forward loop in which p27pTpT/STAT3 co-represses the Pyk2 inhibitor, PTPN12. Pyk2 in turn activates STAT3, driving CSCs expansion. p27pTpT is also shown to critically regulate mammary gland development. Mammary transgenic expression of phosphomimetic, cyclin-CDK binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis and hyperplasia, yielding primary and metastatic breast cancers. This supports a model in which p27pTpT co-regulates STAT3 to drive programs governing stem cell expansion or maintenance in normal and cancer tissues.

2024-04-19 | GSE233351 | GEO

Cisplatin induces the rearrangement of RBPs on CDKN1B/p27 mRNA

Project description:Cisplatin (CP) is a chemotherapeutic drug that is used to cure different types of cancer. CP induces DNA damage and leads to cell cycle arrest. The cyclin-dependent kinase inhibitor 1B (CDKN1B), also termed p27, plays an important role in the drug response ; and increased levels of p27 correlated with CP resistance. In HEK293 cells, we observed that p27 mRNAs levels increased whereas protein level drastically decreased in cells treated with CP; suggesting post-transcriptional regulatory events. To further understand the underlying mechanisms, we applied a biochemical approach combined with mass-spectrometry to systematically identify the RNA-binding proteins (RBPs) that are bound to the 3’UTR of p27 mRNAs in CP-treated versus non-treated cells in vivo. We found that 24 proteins, most of them known RBPs such HuR, hNRNPD, changed their association with p27 mRNA upon CP treatement. Furthermore, knock-down of a subset of the identified RBPs led to the inhibition of the CP-induced increase of p27 mRNA levels. In conclusion, these results highlight substantial rearrangement between RBPs and p27 mRNA upon CP treatment and corroborate the importance of post-transcriptional control in cellular drug response.

2019-09-27 | PXD008498 | Pride

p27-affinity-purified mass spectrometry anslysis

Project description:This project aims to identify p27 modification sites.

2023-01-05 | PXD039223 | Pride

Expression data of NIH3T3 in G0 and G1 phases

Project description:NIH3T3 in the middle of G0 to G1 transion consists of the cells which is still staying G0 phase and the cells which enters G1. Monitoring the expressions of p27 and Cdt1 enables to distinguish these two; p27+/Cdt1+ cells as the cells in G0 phase and p27-Cdt1+ cells as G1 phase We sorted p27+Cdt1+ (G0) NIH3T3 cells and p27-Cdt1+ (G1) NIH3T3 cells in the middle of G0-G1 transition, 5 hours after serum addition following the serum addition using mVenus-p27K- and mCherry-hCdt1(30/120) . We compared the expression profiles of these NIH3T3 cells in G0 and G1 phases and identified the genes upregulated in G0 or G1 phases. The p27+Cdt1+ (G0) NIH3T3 cells and p27-Cdt1+ (G1) NIH3T3 cells were sorted by FACS for RNA extraction and hybridization on Affymetrix microarrays.

2014-02-21 | E-GEOD-46511 | biostudies-arrayexpress

Expression data of NIH3T3 in G0 and G1 phases

2014-02-21 | GSE46511 | GEO

Genome-wide profile of cJun and p27 in breast cancer cells

Project description:We report the genome-wide profile of cJun and p27 in _231 (a line selected for low metastatic ability), _231-1833 (its bone-tropic metastatic derivative line), _231p27CK-DD (a phosphomimetic cell line), and _231-1833shp27 (p27 knockdown cell line). It shows that cJun and p27 broadly binds to genomic DNA and their bindings are regulated by p27 phosphorylation-dependent patterns.

2019-03-19 | GSE112444 | GEO

Rhodococcus sp. P27

Project description:Rhodococcus sp. P27 Genome sequencing and assembly

| PRJNA214615 | ENA

p27 binds to promoters of multiple genes leading to their repression

Project description:The role of the cyclin-cdk inhibitor p27 in tumorigenesis is still a controversial matter. We demonstrate here that p27 negatively regulates transcription of a number of genes (p27-target genes) involved in key cellular functions as RNA processing, translation, respiration and cell proliferation.

2011-12-01 | GSE20068 | GEO

BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein

Project description:Coordinated BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. Persistence of oncogenic p27 functions despite effective inhibition of BCR-ABL1 may contribute to resistance to tyrosine kinase inhibitors. BCR-ABL1 induced p27 versus knockout, controlling with Empty vector p27 versus knock out

2014-10-08 | E-GEOD-59168 | biostudies-arrayexpress

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