This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by García-Jiménez, C. Articles by Santisteban, P. Search for Related Content PubMed PubMed Citation Articles by García-Jiménez, C. Articles by Santisteban, P.

DARPP-32 (Dopamine and 3',5'-Cyclic Adenosine Monophosphate-Regulated Neuronal Phosphoprotein) Is Essential for the Maintenance of Thyroid Differentiation

Instituto de Investigaciones Biomédicas "Alberto Sols" (C.G.-J., M.A.Z., P.S.), Consejo Superior de Investigaciones Cientificas, 28029 Madrid, Spain; and Universidad Rey Juan Carlos (C.G.-J.), Facultad Ciencias de la Salud, 28922 Alcorcón, Madrid Spain

Address all correspondence and requests for reprints to: Custodia García-Jiménez, Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Cientificas, C/Arturo Duperier, 4, 28029 Madrid, Spain. E-mail: custodia.garcia{at}urjc.es.

Coordination of events leading to differentiation is mediated by the concerted action of multiple signal transduction pathways. In general, the uncoupling of mechanisms linking differentiation to cell cycle exit is a hallmark of cancer, yet the identity and regulation of molecules integrating signal transduction pathways remains largely unknown. One notable exception is DARPP-32 (dopamine and cAMP-regulated neuronal phosphoprotein, molecular mass, 32 kDa), a third messenger that integrates multiple signaling pathways in the brain. Thyroid cells represent an excellent model for understanding the coupling of signal transduction pathways leading to both proliferation and differentiation. The cooperative action of IGF-I and TSH together, but not alone, enable thyroid cells to proliferate while maintaining their differentiated state. How signaling downstream from these molecules is integrated is not known. Here we show that DARPP-32 expression is targeted by TSH and IGF-I in thyrocytes. Significantly, dedifferentiated, tumoral, or Ras-transformed thyrocytes fail to express DARPP-32 whereas short interfering RNA-mediated silencing of DARPP-32 expression in normally differentiated thyroid cells results in loss of differentiation markers such as thyroid transcription factor 1, Pax8, thyroglobulin, and the Na/I symporter. Consistently, DARPP-32 reexpression in ras-transformed cells results in reactivation of the otherwise silent thyroglobulin and thyroperoxidase promoter. Thus, DARPP-32 is critical for the maintenance of thyroid differentiation by TSH and IGF-I, and loss of DARPP-32 expression may be a characteristic of thyroid cancer. Our results also raise the possibility that DARPP-32 may play a similar role in the maintenance of differentiation of a range of other cell types.

This article has been cited by other articles:

				C. Hansen, J. Howlin, A. Tengholm, O. Dyachok, W. F. Vogel, A. C. Nairn, P. Greengard, and T. Andersson Wnt-5a-induced Phosphorylation of DARPP-32 Inhibits Breast Cancer Cell Migration in a CREB-dependent Manner J. Biol. Chem., October 2, 2009; 284(40): 27533 - 27543. [Abstract] [Full Text] [PDF]

				M. G. Baratta, I. Porreca, and R. Di Lauro Oncogenic Ras Blocks the cAMP Pathway and Dedifferentiates Thyroid Cells Via an Impairment of Pax8 Transcriptional Activity Mol. Endocrinol., June 1, 2009; 23(6): 838 - 848. [Abstract] [Full Text] [PDF]

				A. Belkhiri, A. A. Dar, A. Zaika, M. Kelley, and W. El-Rifai t-Darpp Promotes Cancer Cell Survival by Up-regulation of Bcl2 through Akt-Dependent Mechanism Cancer Res., January 15, 2008; 68(2): 395 - 403. [Abstract] [Full Text] [PDF]

				G Riesco-Eizaguirre, P Gutierrez-Martinez, M A Garcia-Cabezas, M Nistal, and P Santisteban The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr. Relat. Cancer, March 1, 2006; 13(1): 257 - 269. [Abstract] [Full Text] [PDF]