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BioAssay: AID 588500

Summary assay for small molecule inhibitors of microRNA-mediated mRNA deadenylation

The regulation of gene expression is a mechanism that allows cells to respond to growth and proliferation stimuli, stress, and nutrient availability. It is managed at multiple levels: mRNA expression, mRNA translation initiation and mRNA decay (1). MicroRNAs (miRNAs) are endogenous small RNAs that post-transcriptionally regulate gene expression to control a wide range of biological processes including cell growth, division and differentiation, as well as metabolism and development. ..more
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AID: 588500
Data Source: Burnham Center for Chemical Genomics (SBCCG-A711-MLLE-PAM2-Inh-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2011-10-12
Target
Depositor Specified Assays
AIDNameTypeComment
588489uHTS identification of microRNA-mediated mRNA deadenylation inhibitors by fluoresence polarization assayscreening
602259Dose-response confirmation of microRNA-mediated mRNA deadenylation inhibitors by fluoresence polarization assayconfirmatory
602260Dose-response secondary confirmation of microRNA-mediated mRNA deadenylation inhibitors by fluoresence polarization assay using Cy5 labeled peptideconfirmatory
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Production Centers Network(MLPCN)
Grant Number: R03 MH094198-01
Assay Provider: Kalle Gehring, Ph.D., McGill University

The regulation of gene expression is a mechanism that allows cells to respond to growth and proliferation stimuli, stress, and nutrient availability. It is managed at multiple levels: mRNA expression, mRNA translation initiation and mRNA decay (1). MicroRNAs (miRNAs) are endogenous small RNAs that post-transcriptionally regulate gene expression to control a wide range of biological processes including cell growth, division and differentiation, as well as metabolism and development.

The poly(A) tail of mRNA is bound by several molecules of the poly(A)-binding protein (PABP), an abundant cytoplasmic protein in eukaryotes that promotes translation (2). PABPC1 is a multi-domain protein that contains four phylogenetically conserved RNA recognition motifs (RRM1-4) (3,4) a proline-rich unstructured region and a 70-residue C-terminal domain termed Mlle or PABC (5). Mlle (Mademoiselle) refers to the conserved KITGMLLE signature motif of this domain. The Mlle domain binds proteins with a 12-15 amino acid motif termed PAM2 to regulate PABPC1 involvement in mRNA decay. The goal of this grant is to screen for small molecule modulators of Mlle interactions as chemical probes for the study of PABP regulation in translation and mRNA silencing. This will open new therapeutic opportunities for altering gene expression in cancer, neurodegeneration, and other diseases.

REFERENCES
1. Sonenberg N, Hinnebusch AG. (2007) Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets. Cell 136: 731-745.
2. Kahvejian A, Roy G, Sonenberg N. (2001) The mRNA closed-loop model: the function of PABP and PABP-interacting proteins in mRNA translation. Cold Spring Harbor Symp. Quant. Biol. 66: 293-300.
3. Adam SA, Nakagawa T, Swanson MS, Woodruff TK, Dreyfuss G. (1986) mRNA polyadenylate-binding protein: gene isolation and sequencing and identification of a ribonucleoprotein consensus sequence. Mol. Cell. Biol. 6: 2932-2943.
4. Sachs AB, Davis RW, Kornberg RD. (1987) A single domain of yeast poly(A)-binding protein is necessary and sufficient for RNA binding and cell viability. Mol. Cell. Biol. 7: 3268-3276.
5. Kozlov G, Trempe JF, Khaleghpour K, Kahvejian A, I. Ekiel I, Gehring K. (2001) Structure and function of the C-terminal PABC domain of human poly(A)-binding protein. Proc. Natl Acad. Sci. USA 98: 4409-4413.
Protocol
Please see pertinent AIDs: 588489
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.
Additional Information
Grant Number: R03 MH094198-01

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