Document Detail


Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-kappaB in adult T-cell leukemia/lymphoma.
MedLine Citation:
PMID:  17554373     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) due to human T-cell lymphotropic virus type-1 (HTLV-1) infection. We previously showed that ATLL cells constitutively express high levels of PTHrP via activation of promoters P2 and P3, resulting in HHM. In this study, we characterized a nuclear factor-kappaB (NF-kappaB) binding site in the P2 promoter of human PTHrP. Using electrophoretic mobility shift assays, we detected a specific complex in Tax-expressing human T cells composed of p50/c-Rel, and two distinct complexes in ATLL cells consisting of p50/p50 homodimers and a second unidentified protein(s). Chromatin immunoprecipitation assays confirmed in vivo binding of p50 and c-Rel on the PTHrP P2 promoter. Using transient co-transfection with NF-kappaB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-kappaB p50/p50 alone and p50/c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-kappaB activity by Bay 11-7082 reduced PTHrP P2 promoter-initiated transcripts in HTLV-1-infected T cells. In summary, the data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled by NF-kappaB activation and also suggest a Tax-independent mechanism of activation of PTHrP in ATLL.
Authors:
M V P Nadella; W P Dirksen; K S Nadella; S Shu; A S Cheng; J A Morgenstern; V Richard; S A Fernandez; T H Huang; D Guttridge; T J Rosol
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-06-07
Journal Detail:
Title:  Leukemia     Volume:  21     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-19     Completed Date:  2007-09-25     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1752-62     Citation Subset:  IM    
Affiliation:
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Animals
Blotting, Western
Cell Line, Tumor
Chloramphenicol O-Acetyltransferase
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Gene Expression Regulation, Neoplastic*
HTLV-I Infections / metabolism,  virology
Humans
Leukemia-Lymphoma, Adult T-Cell / genetics*,  metabolism,  pathology
Mice
Mice, Inbred NOD
Mice, SCID
Mutagenesis, Site-Directed
NF-kappa B / physiology*
Parathyroid Hormone-Related Protein / genetics*,  metabolism
Plasmids
Polymerase Chain Reaction
Promoter Regions, Genetic*
RNA, Messenger / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transcriptional Activation
Transfection
Grant Support
ID/Acronym/Agency:
CA100730/CA/NCI NIH HHS; CA77911/CA/NCI NIH HHS; P01 CA100730-01/CA/NCI NIH HHS; RR00168/RR/NCRR NIH HHS; RR07073/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/NF-kappa B; 0/Parathyroid Hormone-Related Protein; 0/RNA, Messenger; EC 2.3.1.28/Chloramphenicol O-Acetyltransferase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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