Genetic interactions and transcriptomics implicate fission yeast CTD prolyl isomerase Pin1 as an agent of RNA 3' processing and transcription termination that functions via its effects on CTD phosphatase Ssu72
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ABSTRACT:
ORGANISM(S): Schizosaccharomyces pombe
PROVIDER: GSE144092 | GEO | 2020/03/20
REPOSITORIES: GEO
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Project description:Mammalian cells possess intrinsic mechanisms to prevent tumorigenesis upon deleterious mutations, including oncogene-induced senescence (OIS). The molecular mechanisms underlying OIS are, however, complex, and remain to be characterized. In this study, we analyzed the changes in the nuclear (phospho)proteome during the progression of OIS. Interestingly, we found that most of the phosphosites regulated during OIS were Prolyl Isomerase Pin1 targets. Our results show that Pin1 is a key regulator of several PML-NB proteins, specifically regulating several proteins upon oncogene activation. We have found that the constitutive PML-NB proteins are significantly regulated when PIN1 is depleted. Furthermore, we show that PIN1 knockdown promotes cell proliferation, while diminishing the senescence phenotype and hallmarks of senescence such as p21. Thus, our data provides preliminary evidence that PML-NB proteins are involved in regulating OIS via phosphorylation, and that the prolyl isomerase PIN1 acts as a tumor suppressor in response to oncogenic ER:RasG12V activation.
| MSV000090326 | MassIVE
Project description:The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provide a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in Eµ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but to the indirect activation of an Arf-p53 dependent cytostatic response. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors. RNAseq samples of Pin1+/+ control (n=4), Pin1 -/- control (n=2), Pin1+/+ Eµ-myc pre-tumoral (n=3), and Pin1-/- Eµ-myc pre-tumoral (n=4) B cells.
2016-06-14 | E-GEOD-77482 | biostudies-arrayexpress
Project description:The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1’s active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement, and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Still, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a suitable chemical probe for assessing Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.
2021-04-01 | GSE166786 | GEO
Project description:The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provide a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in Eµ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but to the indirect activation of an Arf-p53 dependent cytostatic response. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors.
2016-06-14 | GSE77482 | GEO
Project description:The phosphorylation pattern of Pol2 CTD Y1S2P3T4S5P6S7 repeats comprises an informational code coordinating transcription and RNA processing. cis-trans isomerization of CTD prolines expands the scope of the code in ways that are not well understood. Here we address this issue via analysis of fission yeast peptidyl-prolyl isomerase Pin1. A pin1Δ allele that does not affect growth per se is lethal in the absence of cleavage-polyadenylation factor (CPF) subunits Ppn1 and Swd22 and elicits growth defects absent CPF subunits Ctf1 and Dis2 and termination factor Rhn1. Whereas CTD S2A, T4A, and S7A mutants thrive in combination with pin1Δ, a Y1F mutant does not, nor do CTD mutants in which half the Pro3 or Pro6 residues are replaced by alanine. Phosphate-acquisition genes pho1, pho84 and tgp1 are repressed by upstream lncRNAs and are sensitive to changes in lncRNA 3' processing/termination. pin1Δ hyper-represses PHO gene expression and erases the de-repressive effect of CTD-S7A. Transcriptional profiling delineated sets of 56 and 22 protein-coding genes that are down-regulated and up-regulated in pin1Δ cells, respectively, 77% and 100% of which are downregulated/upregulated when the cis-proline-dependent Ssu72 CTD phosphatase is inactivated. Our results implicate Pin1 as a positive effector of 3' processing/termination that acts via Ssu72.
| S-EPMC7229847 | biostudies-literature
Project description:The prolyl isomerase PIN1 has been identified as a regulator of phosphorylation signalling that catalyses the conversion of specific phosphorylated motifs between the two completely distinct conformations in a subset of proteins. PIN1 regulates diverse cellular processes, including growth-signal responses, cell-cycle progression, cellular stress responses, neuronal function and immune responses. We used microarrays to detail the global gene expression of mammary epithelial cells (MECs) and neuron cells (NCs) in Pin1 KO and WT mice
2015-03-26 | GSE49971 | GEO
Project description:Pin1 is a prolyl isomerase that plays an important role in cancer, Alzheimer's disease, and asthma. To understand how Pin1 levels affect mRNA abundance on a genome-wide scale, we knocked down Pin1 by siRNA and used microarray-based gene expression profiling to identify candidate genes that are significantly up- or down-regulated by Pin1 siRNA. The data provide important information on Pin1-responsive genes. We find that genes that are inherently unstable and have short half-lives are targeted by Pin1.
2012-10-27 | GSE41868 | GEO
Project description:Pin1 is a prolyl isomerase that plays an important role in cancer, Alzheimer's disease, and asthma. To understand how Pin1 levels affect mRNA abundance on a genome-wide scale, we knocked down Pin1 by siRNA and used microarray-based gene expression profiling to identify candidate genes that are significantly up- or down-regulated by Pin1 siRNA. The data provide important information on Pin1-responsive genes. We find that genes that are inherently unstable and have short half-lives are targeted by Pin1. Total RNA was obtained from HeLa cells treated with either control siRNA or an siRNA towards Pin1. There were three replicates each for the control and the siRNA-treated cells. The average signal for the three replicates is reported.
2012-10-27 | E-GEOD-41868 | biostudies-arrayexpress
Project description:Bladder cancer, one of the most diagnosed cancers worldwide, is associated with high morbidity, mortality, and a poor prognosis. The PIN1 phospho-dependent prolyl isomerase is frequently overexpressed in many human cancer types and affects tumor initiation and progression through disrupting the balance of oncoprotein and tumor suppressor protein signaling. However, the functional pSer/Thr.Pro protein substrates of PIN1 and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we discovered that ablation of Pin1 in human/mouse bladder cancer cells and organoids formed from mouse primary urothelial cells resulted in decreased cell proliferation, stemness maintenance, cell invasion, migration, urothelium clearance capacity, and reduced free/total cholesterol levels in vitro. Re-expressing Pin1 in Pin1 knockout cells reversed the defects caused by lack of Pin1. Moreover, in vivo subcutaneous xenograft and allograft transplantation mouse models combined with an orthotopic implantation model were utilized to confirm a positive role for Pin1 in controlling tumor growth and potential metastasis. Therapeutically, a combination of the sulfopin PIN1 inhibitor and the simvastatin HMGCR inhibitor was shown to suppress cell proliferation in vitro and tumor growth in vivo synergistically. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways in PIN1 knockout cells via RNA-sequencing and used a suite of diverse molecular and biochemical approaches to show that PIN1 interacts with JNK-dependent phosphorylated SREBP2 (Ser455) and vice versa. These results indicate that active cholesterol biosynthesis pathway in bladder cancer cells is regulated by PIN1-mediated isomerization and JNK-mediated phosphorylation of its key transcriptional factor SREBP2. These findings emphasize that PIN1 can act as a regulator and potential therapeutic target in bladder cancer.
2024-11-17 | GSE262761 | GEO
Project description:Genetic interactions and transcriptomics implicate fission yeast CTD prolyl isomerase Pin1 as an agent of RNA 3' processing and transcription termination that functions via its effects on CTD phosphatase Ssu72
| PRJNA602734 | ENA