Linked Life Data

16849550

Source:http://linkedlifedata.com/resource/pubmed/id/16849550

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2006-7-19
pubmed:abstractText
EphA2 receptor tyrosine kinase is frequently overexpressed in different human cancers, suggesting that it may promote tumor development and progression. However, evidence also exists that EphA2 may possess antitumorigenic properties, raising a critical question on the role of EphA2 kinase in tumorigenesis in vivo. We report here that deletion of EphA2 in mouse led to markedly enhanced susceptibility to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. EphA2-null mice developed skin tumors with an increased frequency and shortened latency. Moreover, tumors in homozygous knockout mice grew faster and were twice as likely to show invasive malignant progression. Haploinsufficiency of EphA2 caused an intermediate phenotype in tumor development but had little effects on invasive progression. EphA2 and ephrin-A1 exhibited compartmentalized expression pattern in mouse skin that localized EphA2/ephrin-A1 interactions to the basal layer of epidermis, which was disrupted in tumors. Loss of EphA2 increased tumor cell proliferation, whereas apoptosis was not affected. In vitro, treatment of primary keratinocytes from wild-type mice with ephrin-A1 suppressed cell proliferation and inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) activities. Both effects were abolished in EphA2-null keratinocytes, suggesting that loss of ERK inhibition by EphA2 may be one of the contributing mechanisms for increased tumor susceptibility. Interestingly, despite its tumor suppressive function, EphA2 was overexpressed in skin tumors compared with surrounding normal skin in wild-type mice, similar to the observations in human cancers. EphA2 overexpression may represent a compensatory feedback mechanism during tumorigenesis. Together, these results show that EphA2 is a novel tumor suppressor gene in mammalian skin.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
66
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7050-8
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16849550-9,10-Dimethyl-1,2-benzanthracene, pubmed-meshheading:16849550-Animals, pubmed-meshheading:16849550-Carcinogens, pubmed-meshheading:16849550-Cell Growth Processes, pubmed-meshheading:16849550-Cell Transformation, Neoplastic, pubmed-meshheading:16849550-Enzyme Activation, pubmed-meshheading:16849550-Ephrin-A1, pubmed-meshheading:16849550-Female, pubmed-meshheading:16849550-Genetic Predisposition to Disease, pubmed-meshheading:16849550-Keratinocytes, pubmed-meshheading:16849550-Mice, pubmed-meshheading:16849550-Mice, Inbred C57BL, pubmed-meshheading:16849550-Mice, Knockout, pubmed-meshheading:16849550-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:16849550-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:16849550-Receptor, EphA2, pubmed-meshheading:16849550-Skin, pubmed-meshheading:16849550-Skin Neoplasms, pubmed-meshheading:16849550-Tetradecanoylphorbol Acetate
pubmed:year
2006
pubmed:articleTitle
Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin.
pubmed:affiliation
Rammelkamp Center for Research and Department of Pharmacology and Comprehensive Cancer Center.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural