Elevated p53 Activaties Restrict Differentiation Potential of microRNA-deficient Pluripotent Stem Cells
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PROVIDER: PRJNA413063 | ENA |
REPOSITORIES: ENA
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Project description:Pluripotent stem cells (PSCs) deficient for microRNAs (miRNAs), such as Dgcr8-/- or Dicer-/- embryonic stem cells (ESCs), contain no mature miRNA and cannot differentiate into somatic cells. How miRNA deficiency causes differentiation defects remains poorly understood. Here, we report that miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8-/- ESCs. Our data showed that miR-302 directly suppresses the tumor suppressor p53, which is modestly upregulated in Dgcr8-/- ESCs and serves as a barrier restricting neural differentiation. We demonstrated that direct inactivation of p53 by SV40 large T antigen, a short hairpin RNA against Trp53, or genetic ablation of Trp53 in Dgcr8-/- PSCs enables neural differentiation, while activation of p53 by the MDM2 inhibitor nutlin-3a in wild-type ESCs inhibits neural differentiation. Together, we demonstrate that a major function of miRNAs in neural differentiation is suppression of p53 and that modest activation of p53 blocks neural differentiation of miRNA-deficient PSCs.
2017-11-21 | GSE104569 | GEO
Project description:Pluripotent stem cells (PSCs) deficient for microRNAs (miRNAs), such as Dgcr8-/- or Dicer-/- embryonic stem cells (ESCs), contain no mature miRNA and cannot differentiate into somatic cells. How miRNA deficiency causes differentiation defects remains poorly understood. Here, we report that miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8-/- ESCs. Our data showed that miR-302 directly suppresses the tumor suppressor p53, which is modestly upregulated in Dgcr8-/- ESCs and serves as a barrier restricting neural differentiation. We demonstrated that direct inactivation of p53 by SV40 large T antigen, a short hairpin RNA against Trp53, or genetic ablation of Trp53 in Dgcr8-/- PSCs enables neural differentiation, while activation of p53 by the MDM2 inhibitor nutlin-3a in wild-type ESCs inhibits neural differentiation. Together, we demonstrate that a major function of miRNAs in neural differentiation is suppression of p53 and that modest activation of p53 blocks neural differentiation of miRNA-deficient PSCs.
| S-EPMC5688240 | biostudies-other
Project description:p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germ line tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5’UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.
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Project description:Unbalanced and growth promoting cell fate dynamics that follow p53 loss, and the inability of canonical p53 functions to restrict clonal expansion, suggest the existence of a non-canonical p53 transcriptional program that controls key cell fate regulators. We hypothesized that these cell fate genes are among the shared targets of p53WT and p533KR.
2024-08-31 | GSE275726 | GEO
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Project description:We report the expression anaysis of neural stem cells lacking p53, ATMIN, or both. p53-deficent cells form GBM, which is significanly delayed in the absence of ATMIN.
2015-12-23 | GSE76296 | GEO
Project description:p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.
2024-08-05 | GSE273169 | GEO
Project description:P53 induced Mir34a is a tumor suppressor microRNA that plays important roles in cancer related processes such as proliferation, invasion and metastasis. Simultaneous loss of Mir34a and p53 is often observed in CRC. Here we show that, combined deletion of Mir34a and p53 has synergistic effects in suppressing tumor initiation, progression, invasion and metastasis in CRC by using mice lacking Mir34a and p53 in their intestinal epithelium. By in vivo inhibition of IL6R and SERPINE1, which we identified as up-regulated Mir34a targets in tumors of Mir34a/p53 deficient mice, we obtained preclinical evidence for their therapeutic value for treatment of sporadic CRC.
2018-08-31 | GSE99452 | GEO
Project description:The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients.
2024-07-01 | GSE238231 | GEO
Project description:The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients.
2024-07-01 | GSE238230 | GEO