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J. Biol. Chem., Vol. 280, Issue 39, 33541-33551, September 30, 2005

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Cyclic AMP-mediated Regulation of Transcription Factor Lot1 Expression in Cerebellar Granule Cells^*

From the Department of Human and General Physiology, University of Bologna, 40126 Bologna, Italy

Lot1, a zinc finger transcription factor acting as a tumor suppressor gene on tumoral cells, is highly expressed during brain development. In developing rat cerebellum, Lot1 expression is high in cerebellar granule cells (CGC), a neuronal population undergoing postnatal neurogenesis. The time course of Lot1 cerebellar expression closely matches the expression of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors coupled to adenylyl cyclase. The aim of this study was to ascertain whether Lot1 expression is regulated by cAMP-dependent pathways and to identify mechanisms of Lot1 activation in CGC cultures. Our results show that Lot1 expression in CGC is cAMP-dependent, as treatments with either forskolin or PACAP-38 induced an increase in its expression at both the mRNA and protein levels. This effect on Lot1 expression was mimicked by dibutyryl cAMP and suppressed by protein kinase A and MEK inhibitors. In parallel, we found that treatments with forskolin and PACAP-38 in precursor CGC inhibited bromodeoxyuridine incorporation by 25 and 35%, respectively, indicating a negative effect on neuronal precursor proliferation. Luciferase reporter analysis and mutagenesis of the Lot1 promoter region indicated a crucial role of the AP1-binding site (located at -268 bp) in cAMP-induced Lot1 transcription. In addition, cotransfection experiments indicated that the c-Fos/c-Jun heterodimer is responsible for cAMP-dependent Lot1 transcriptional activation. In conclusion, our data demonstrate that, in CGC, Lot1 is under the transcriptional control of cAMP through an AP1 site regulated by the c-Fos/c-Jun heterodimer and suggest that this gene may be an important element of the cAMP-mediated pathway that regulates neuronal proliferation through the protein kinase A-MEK signaling cascade.

Received for publication, November 26, 2004 , and in revised form, July 19, 2005.

^* This work was supported by a Young Investigator grant (to E. C.) and by funding for basic research (to R. B.) from the University of Bologna. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Human and General Physiology, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy. Tel.: 39-051-209-1721; Fax: 39-051-251-731; E-mail: elisabetta.ciani{at}unibo.it.

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				T. Fila, S. Trazzi, C. Crochemore, R. Bartesaghi, and E. Ciani Lot1 Is a Key Element of the Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/Cyclic AMP Pathway That Negatively Regulates Neuronal Precursor Proliferation J. Biol. Chem., May 29, 2009; 284(22): 15325 - 15338. [Abstract] [Full Text] [PDF]