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Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE77482 | GEO | 2016/06/14

SECONDARY ACCESSION(S): PRJNA310614

REPOSITORIES: GEO

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Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc

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 EÂµ-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+/+ EÂµ-myc pre-tumoral (n=3), and Pin1-/- EÂµ-myc pre-tumoral (n=4) B cells.

2016-06-14 | E-GEOD-77482 | biostudies-arrayexpress

Substrate selectivity for semisynthetic CK2 proteins with Pin1

Project description:Protein Ser/Thr kinase CK2 is involved in a myriad of cellular processes including cell growth and proliferation by phosphorylating hundreds of substrates, yet the regulation process of CK2 function is poorly understood. The CK2 catalytic subunit, CK2α, is phosphorylated at Thr344 and phosphorylation on the C-terminal tail of CK2α is required for interaction with Pin1 protein. The substrate selectivity for protein kinase CK2α was examined by performing kinase assays on protein microarrays spotted with 17,000 human proteins. Semisynthetic CK2α proteins were prepared to contain an unmodified C-terminal tail or phospho-Thr (pThr) at T344. These semisynthetic proteins were used to determine if the phosphorylation-dependent interaction of CK2α with Pin1 can modulate the substrate selectivity for CK2. The different semisynthetic CK2α proteins (unmodified and pThr344) were tested alone and in the presence of the recombinant Pin1 protein. Pin1 has been shown to interaction with CK2α only when CK2α is phoshorylated on its C-terminal site (including Thr344). In the study presented here, kinase assays were performed using two different semisynthetic CK2α proteins: unmodified C-terminal tail and phospho-Thr (pThr) at 344. The semisynthetic proteins were each tested alone and in the presence of the recombinant Pin1 protein. There were four different kinase conditions and each condition was performed in duplicate.

2011-10-24 | E-GEOD-33150 | biostudies-arrayexpress

Substrate selectivity for semisynthetic CK2 proteins with Pin1

2011-10-25 | GSE33150 | GEO

Expression data from Pin1 KO and WT mice

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

Expression data from Pin1 inhibitor ATRA and Pin1 knockdown

Project description:ATRA was identified as a Pin1 inhibitor via fluorescence polarization-based high throughput screening. We performed microarray expression profiling to demonstrate the similarity between ATRA and Pin1 KD at the genome-wide level APL NB4 cells in response to ATRRA or inducible Pin1 knockdown for 3 days were collected for RNA extraction and hybridization on Affymetrix microarrays. We sought to validate in genome-wide level whether similarity occurred between ATRA and Pin1 knockdown-treated NB4 cells.

2015-04-12 | E-GEOD-63059 | biostudies-arrayexpress

Effect of global MYC DNA binding due to loss of PIN1

Project description:The goal of this study was to determine the MYC binding difference between WT and PIN1 knockout mouse embryonic fibroblasts.

2018-11-20 | GSE109458 | GEO

Sulfopin, a covalent inhibitor of Pin1, blocks Myc-driven tumors in vivo

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

Expression data from Pin1 inhibitor ATRA and Pin1 knockdown

2015-04-12 | GSE63059 | GEO

Pin1/mutant-p53 jointly controlled genes

Project description:To investigate the specific gene expression program by which mutant-p53 and Pin1 control invasion and metastasis in breast cancer cells, we compared the transcriptomic profile of control, mutant-p53 depleted or Pin1 depleted MDA-MB-231 cells.

2011-05-30 | GSE26262 | GEO

Suppression of pid nulls by mutations in PIN-FORMED1 (PIN1) and PIN1-GFP fusion

Project description:Disruption of either the auxin transporter PIN-FORMED 1 (PIN1) or the protein kinase PINOID (PID) leads to the development of pin-like inflorescences. Previous studies suggested that PID phosphorylates and activates PIN1. Here we report unexpected findings about the genetic interactions between the two genes. We deleted the first 2/3 of the PIN1 coding sequence using CRISPR/Cas9 and the resulting pin1 mutant (pin1-27) was a strong allele. Surprisingly, heterozygous pin1-27 suppressed three independent pid null mutants whereas homozygous pin1-27 enhanced the phenotypes of the pid mutants during embryogenesis. Furthermore, we show that deletion of either the hydrophilic loop or the second half of PIN1 also abolished PIN1 function, yet those heterozygous pin1 mutants were also capable of rescuing pid nulls. Moreover, we inserted GFP into the hydrophilic loop of PIN1 through CRISPR-mediated homology-directed repair (HDR). The GFP signal and pattern in the PIN1-GFP HDR line are similar to those in the previously reported PIN1-GFP transgenic lines. Interestingly, the PIN1-GFP HDR line also rescued various pid null mutants in a semi-dominant fashion. In addition, the previously reported key phosphorylation sites in PIN1 were still phosphorylated in PIN1-GFP pid plants. We conclude that PID is not directly required for phosphorylation and activation of PIN1.

2023-07-07 | MSV000092373 | MassIVE

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