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Inhibition of Zac1, a New Gene Differentially Expressed in the Anterior Pituitary, Increases Cell Proliferation¹

Max Planck Institute of Psychiatry (U.P., E.C., F.L., D.S., G.K.S.), 80804 Munich; and the Departments of Neurology, Technical University of Munich (T.A.), 81675 Munich, Germany; Centre National de la Recherche Scientifique (L.J., D.S.), 34094 Montpellier Cedex 05, France; and the Institute of Semeiotica Medica, University of Padua (C.P.), Padua, Italy

Address all correspondence and requests for reprints to: Uberto Pagotto, M.D., Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. E-mail: pagotto{at}mpipsykl.mpg.de

Zac1 is a new zinc finger protein that concomitantly controls apoptosis and cell cycle arrest through separate pathways. The mouse Zac1 gene is mainly expressed in the pituitary gland and in different brain areas. In this study regional and cellular expression of Zac1 in the pituitary gland was determined by in situ hybridization. Zac1 messenger RNA was abundantly expressed in the anterior pituitary lobe compared with that in the intermediate and posterior lobes. Zac1 transcripts were found in all hormone-secreting cell types, with the highest levels in GH- and PRL-producing cells.

To investigate the impact of Zac1 in pituitary cell proliferation, we ablated the endogenous Zac1 gene by antisense treatment in two murine cell types, AtT-20 and TtT/GF, that are representative of granular and agranular cell lineages, respectively. The decline in Zac1 protein levels under antisense treatment was accompanied by increased DNA synthesis in clonal corticotroph and folliculo-stellate cells, as demonstrated by enhanced [³H]thymidine incorporation (36% and 50%, respectively). Antisense oligonucleotides against Zac1 controlled cell proliferation in a dose-dependent way, and mutagenized antisense oligonucleotides were inert. Conclusively, our data provide the first evidence of a role for Zac1 in pituitary growth control.

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