title: Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism.
abstract: In secondary hyperparathyroidism, enhanced expression of TGF-alpha in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-alpha activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2alpha (AP2), an inducer of TGF-alpha gene transcription, in the upregulation of parathyroid TGF-alpha in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-alpha levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-alpha induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-alpha and TGF-alpha self-induction, mutating the core AP2 site of the human TGF-alpha promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-alpha. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-alpha self-induction using erlotinib, a highly specific inhibitor of TGF-alpha/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-alpha and are required for TGF-alpha self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-alpha self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-alpha mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-alpha promoter determine the severity of the hyperplasia driven by parathyroid TGF-alpha self-upregulation in secondary hyperparathyroidism.
authors.affiliation: Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Arcidiacono
authors.forename: Mario
authors.initials: M
authors.lastname: Cozzolino
authors.forename: Noah
authors.initials: N
authors.lastname: Spiegel
authors.forename: Masanori
authors.initials: M
authors.lastname: Tokumoto
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Sato
authors.forename: Carlo
authors.initials: C
authors.lastname: Lomonte
authors.forename: Carlo
authors.initials: C
authors.lastname: Basile
authors.forename: Eduardo
authors.initials: E
authors.lastname: Slatopolsky
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Dusso
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010280:Parathyroid Glands / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D014511:Uremia / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D050656:Transcription Factor AP-2; D016211:Transforming Growth Factor alpha