Unknown,Transcriptomics,Genomics,Proteomics

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MicroRNA expression profiling of mouse NOTCH1-induced tumors following in vivo treatment with gamma-secretase inhibitor

ABSTRACT: NOTCH1 is a transcription factor involved in T-cell development and mutations that occur in NOTCH1 gene affects more than 60% of patients affected by T-cell acute lymphoblastic leukemia (T-ALL). In order to identify microRNAs regulated following NOTCH1 inhibition in T-ALL, murine NOTCH1-induced T-cell leukemia were treated with a NOTCH1 inhibitor (DBZ, Dibenzazepine). Tumors were established in irradiated C57BL/6 mice injected with lineage negative progenitors cells transduced with a mutated NOTCH1 allele (HD-ΔPEST NOTCH1). Mice were treated three times, 8 hours apart, with vehicle only (DMSO) or DBZ (5mg/Kg). Total RNA was extracted from tumor samples (spleens of sick mice) and hybridized on Agilent mouse miRNA 8x60K arrays (release 19.0). Each sample was derived from a different mouse (n=3 mice/group). Raw microarray data, preprocessed data matrix and results of differential expression analysis are available together with the applied protocols.

ORGANISM(S): Mus musculus

SUBMITTER: Angela Grassi

PROVIDER: E-MTAB-9278 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice.

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MicroRNA expression profiling of mouse NOTCH1-induced tumors following in vivo treatment with gamma-secretase inhibitor

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