Linked Life Data

21273305

Source:http://linkedlifedata.com/resource/pubmed/id/21273305

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2011-4-1
pubmed:abstractText
Activating mutations in codon D816 of the tyrosine kinase receptor, KIT, are found in the majority of patients with systemic mastocytosis. We found that the transcription factor, microphthalmia-associated transcription factor (MITF), is highly expressed in bone marrow biopsies from 9 of 10 patients with systemic mastocytosis and activating c-KIT mutations. In primary and transformed mast cells, we show that KIT signaling markedly up-regulates MITF protein. We demonstrate that MITF is required for the proliferative phenotype by inhibiting colony-forming units with sh-RNA knockdown of MITF. Furthermore, constitutively active KIT does not restore growth of primary MITF-deficient mast cells. MITF mRNA levels do not change significantly with KIT signaling, suggesting posttranscriptional regulation. An array screen from mast cells identified candidate miRNAs regulated by KIT signaling. We found that miR-539 and miR-381 are down-regulated by KIT signaling and they repressed MITF expression through conserved miRNA binding sites in the MITF 3'-untranslated region. Forced expression of these miRNAs suppressed MITF protein and inhibited colony-forming capacity of mastocytosis cell lines. This work demonstrates a novel regulatory pathway between 2 critical mast cell factors, KIT and MITF, mediated by miRNAs; dysregulation of this pathway may contribute to abnormal mast cell proliferation and malignant mast cell diseases.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1528-0020
pubmed:author
pubmed:issnType
Electronic
pubmed:day
31
pubmed:volume
117
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3629-40
pubmed:meshHeading
pubmed-meshheading:21273305-Animals, pubmed-meshheading:21273305-Antineoplastic Agents, pubmed-meshheading:21273305-Cell Proliferation, pubmed-meshheading:21273305-Cells, Cultured, pubmed-meshheading:21273305-Gene Expression Regulation, pubmed-meshheading:21273305-Humans, pubmed-meshheading:21273305-Mast Cells, pubmed-meshheading:21273305-Mastocytosis, Systemic, pubmed-meshheading:21273305-Mice, pubmed-meshheading:21273305-Mice, Inbred C57BL, pubmed-meshheading:21273305-Mice, Knockout, pubmed-meshheading:21273305-MicroRNAs, pubmed-meshheading:21273305-Microphthalmia-Associated Transcription Factor, pubmed-meshheading:21273305-NIH 3T3 Cells, pubmed-meshheading:21273305-Piperazines, pubmed-meshheading:21273305-Proto-Oncogene Proteins c-kit, pubmed-meshheading:21273305-Pyrimidines, pubmed-meshheading:21273305-Signal Transduction, pubmed-meshheading:21273305-Staurosporine
pubmed:year
2011
pubmed:articleTitle
KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation.
pubmed:affiliation
Pediatric Hematology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural