Linked Life Data

19201832

Source:http://linkedlifedata.com/resource/pubmed/id/19201832

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2009-2-9
pubmed:abstractText
Resistance to growth suppression by TGF-beta1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G(1) cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1550-6606
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
182
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1810-7
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:19201832-Apoptosis, pubmed-meshheading:19201832-Bone Marrow Cells, pubmed-meshheading:19201832-Cyclin-Dependent Kinase 2, pubmed-meshheading:19201832-Enzyme-Linked Immunosorbent Assay, pubmed-meshheading:19201832-Gene Expression Regulation, pubmed-meshheading:19201832-Humans, pubmed-meshheading:19201832-Immunoblotting, pubmed-meshheading:19201832-Immunoprecipitation, pubmed-meshheading:19201832-Multiple Myeloma, pubmed-meshheading:19201832-Phosphorylation, pubmed-meshheading:19201832-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:19201832-Signal Transduction, pubmed-meshheading:19201832-Smad2 Protein, pubmed-meshheading:19201832-Transcription, Genetic, pubmed-meshheading:19201832-Transfection, pubmed-meshheading:19201832-Transforming Growth Factor beta
pubmed:year
2009
pubmed:articleTitle
CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells.
pubmed:affiliation
Department of Pathology, Weill Medical College of Cornell University, New York, NY 10065, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural