Document Detail


Human skin neural crest progenitor cells are susceptible to BRAF(V600E)-induced transformation.
MedLine Citation:
PMID:  23334329     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adult stem cells are multipotent and persist in small numbers in adult tissues throughout the lifespan of an organism. Unlike differentiated cells, adult stem cells are intrinsically resistant to senescence. It is unclear how adult stem cells in solid organs respond to oncogenic stimulation and whether these cells have a role in tumor initiation. We report here that expression of BRAF(V600E) in human neural crest progenitor cells (hNCPCs) did not induce growth arrest as seen in human melanocytes, but instead, increased their cell proliferation capacity. These cells (hNCPCs(V600E)) acquired anchorage-independent growth ability and were weakly tumorigenic in vivo. Unlike in human melanocytes, BRAF(V600E) expression in hNCPCs did not induce p16(INK4a) expression. BRAF(V600E) induced elevated expression of CDK2, CDK4, MITF and EST1/2 protein in hNCPCs, and also induced melanocytic differentiation of these cells. Furthermore, overexpression of MITF in hNCPCs(V600E) dramatically increased their tumorigenicity and resulted in fully transformed tumor cells. These findings indicate that hNCPCs are susceptible to BRAF(V600E)-induced transformation, and MITF potentiates the oncogenic effect of BRAF(V600E) in these progenitor cells. These results suggest that the hNCPCs are potential targets for BRAF(V600E)-induced melanocytic tumor formation.
Authors:
S M Kumar; J Dai; S Li; R Yang; H Yu; K L Nathanson; S Liu; H Zhou; J Guo; X Xu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-21
Journal Detail:
Title:  Oncogene     Volume:  33     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-02-13     Completed Date:  2014-04-14     Revised Date:  2014-05-02    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  832-41     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult Stem Cells / metabolism*,  pathology
Animals
Cell Proliferation
Cell Transformation, Neoplastic / genetics*,  metabolism,  pathology
Cells, Cultured
DNA Copy Number Variations
Female
Gene Expression
Humans
Male
Melanoma / genetics,  metabolism,  pathology
Mice, Inbred NOD
Mice, SCID
Microphthalmia-Associated Transcription Factor / genetics
Mutation, Missense
Neoplasm Transplantation
Neural Crest / pathology*
Neural Stem Cells / metabolism*,  pathology
Phenotype
Proto-Oncogene Proteins B-raf / genetics*,  metabolism
Skin / pathology*
Tumor Burden
Grant Support
ID/Acronym/Agency:
AR-054593/AR/NIAMS NIH HHS; CA-116103/CA/NCI NIH HHS; P01 CA025874/CA/NCI NIH HHS; P01 CA114046/CA/NCI NIH HHS; P30 CA016520/CA/NCI NIH HHS; R01 AR054593/AR/NIAMS NIH HHS; R21 CA116103/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/MITF protein, human; 0/Microphthalmia-Associated Transcription Factor; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf

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