rdf:type |
|
lifeskim:mentions |
umls-concept:C0017262,
umls-concept:C0034678,
umls-concept:C0086418,
umls-concept:C0109317,
umls-concept:C0185117,
umls-concept:C0281361,
umls-concept:C0694888,
umls-concept:C0752312,
umls-concept:C1150579,
umls-concept:C1333340,
umls-concept:C1366882,
umls-concept:C1370600,
umls-concept:C1510779,
umls-concept:C1705767,
umls-concept:C1705791,
umls-concept:C2911684
|
pubmed:issue |
11
|
pubmed:dateCreated |
2007-11-6
|
pubmed:abstractText |
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.
|
pubmed:grant |
|
pubmed:language |
eng
|
pubmed:journal |
|
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN Phosphohydrolase,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins p21(ras),
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta
|
pubmed:status |
MEDLINE
|
pubmed:month |
Nov
|
pubmed:issn |
1460-2180
|
pubmed:author |
|
pubmed:issnType |
Electronic
|
pubmed:volume |
28
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
2321-7
|
pubmed:dateRevised |
2011-9-22
|
pubmed:meshHeading |
pubmed-meshheading:17638924-Blotting, Western,
pubmed-meshheading:17638924-Cell Line,
pubmed-meshheading:17638924-Flavonoids,
pubmed-meshheading:17638924-Humans,
pubmed-meshheading:17638924-Mitogen-Activated Protein Kinases,
pubmed-meshheading:17638924-PTEN Phosphohydrolase,
pubmed-meshheading:17638924-Pancreatic Neoplasms,
pubmed-meshheading:17638924-Protein Kinase Inhibitors,
pubmed-meshheading:17638924-Proto-Oncogene Proteins p21(ras),
pubmed-meshheading:17638924-RNA, Messenger,
pubmed-meshheading:17638924-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:17638924-Smad4 Protein,
pubmed-meshheading:17638924-Transforming Growth Factor beta
|
pubmed:year |
2007
|
pubmed:articleTitle |
RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.
|
pubmed:affiliation |
Division of Gastroenterology, Department of Medicine, University of California, San Diego, MC 0063, 9500 Gilman Drive, La Jolla, CA 92093-0063, USA.
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|