Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Constitutively active STAT5 recruits p53 to alternative transcriptional targets in myeloid cancers

ABSTRACT: In several cancer types, STAT (Signal transducer and activator of transcription) transcription factors are constitutively activated. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. Here, we demonstrate in transformed hematopoietic cells that binding of both STAT5B and p53 to chromatin is required for transcriptional activity of an alternative LPP/miR-28 promoter. Using a genome-wide approach, we identified 463 genomic positions at promoter regions where STAT5B and p53 are co-localized on the chromatin. At these positions, p53 chromatin binding is dependent on persistent STAT5B activation. The transcriptional activity of selected promoters bound by STAT5B and p53 was significantly changed upon STAT5 or p53 inhibition, and the transcription of these target genes is frequently altered in platelets of myeloproliferative neoplasm patients harboring mutations constitutively activating STAT5. These data suggest that the constitutive STAT5 activation recruits p53 in cancer cells and thereby activates oncogenic transcriptional programs. STAT5B and p53 ChIP-chip with or without JAK2 inhibition (ruxolitinib) to inhibit STAT5 phosphorylation and DNA binding.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Girardot

PROVIDER: E-GEOD-38143 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:MarekM-bM-^@M-^Ys disease virus (MDV) is an oncovirus causing tumor disease known as MarekM-bM-^@M-^Ys disease (MD) in chicken. Breeding of chickens genetically resistant to MD is considered a vital augment to better control MD. To find the mechanism underlying the genetic resistance to MD, a genomic structural variation, copy number variation (CNV), was examined in inbred MD-resistant and -susceptible chicken lines by using the comparative genomic hybridization (CGH) technique. A total of 45 copy number variation regions (CNVRs) were found spanning across 3,297,038 bp in length of the chicken genome in 4 lines of chickens. Ten CNVRs were selectively confirmed with quantitative real-time PCR. The comparison between the resistant and susceptible chicken lines revealed 28 differentially presented CNVRs, which are functionally involved in immune response, cell proliferation in midbrain, G-protein coupled receptor signaling pathway, and protein-glutamine gamma-glutamyltransferase activity. Two CNVRs that are related with MD-resistance and M-bM-^@M-^Ssusceptibility were also found transmitted to descendent recombinant congenic lines that differ in susceptibility to MD. A positive correlation was identified between the CNVRs and gene expression, indicating the importance of gene expression dosage in disease resistance. We also found the overlapping between the CNVR region and the MarekM-bM-^@M-^Ys disease trait related quantitative trait loci (QTLs). In conclusion, our data provided additional information elucidating one of possible mechanisms underlying of genetic resistance to MD. The findings may eventually lead to better strategies for genetic improvement of resistance to MD in poultry. L63: highly resistant to MD; L72: highly susceptible to MD; RCS-L: moderate resistant to MD; RCS-M: moderate susceptible to MD Red blood cell DNAs were isolated from L63, L72, RCS-L and RCS-M and then labeled with Cy3. DNA from Red Junglefowl was labeled with Cy5 as reference and mixed with Cy3 labeled DNA, then hybridized to the 385K chicken tiling array. The hybridization, normalization and segmentation analysis were performed by NimbleGen Systems Inc. (Madison, USA). A detailed description of their technical specifics can be found on http://www.nimblegen.com/products/lit/lit.html. Briefly, the segments with five or more probes having a mean log2 ratio greater than M-BM-10.5 (0.5_5) were chosen as candidate CNVs.

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Constitutively active STAT5 recruits p53 to alternative transcriptional targets in myeloid cancers

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