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Neuroendocrine Cell Type-Specific and Inducible Expression of the Secretogranin II Gene: Crucial Role of Cyclic Adenosine Monophosphate and Serum Response Elements¹

Department of Medicine and Center for Molecular Genetics (S.K.M., M.M., C.V.L., D.T.O’C.), University of California, and San Diego VA Healthcare System, San Diego, California 92161; and Department of Neurobiology, Heidelberg University (H.-H.G., W.B.H.), Heidelberg, Germany

Address all correspondence and requests for reprints to: Sushil K. Mahata, Ph.D., Department of Medicine and Center for Molecular Genetics (9111H), University of California, San Diego, 3350 La Jolla Village Drive, San Diego, California 92161-9111H. E-mail: smahata{at}ucsd.edu

Secretogranin II, an acidic protein in the chromogranin/secretogranin family, is widely distributed in neuroendocrine secretory granules. What factors govern such widespread, yet selective, expression? The 5' deletions localized neuroendocrine cell type-specific expression to the proximal mouse secretogranin II promoter: such expression was abolished after deletion past the cAMP response element (CRE; [-67 bp]TGACGTCA[-60 bp]), and transfer of the CRE to a neutral promoter conferred 3.4- to 5.3-fold neuroendocrine selectivity. Thus, the CRE is, at least partly, sufficient to confer tissue-specific expression. Substantial (48–59%) loss of cell type-specific expression also occurred upon deletion past the serum response element (SRE; [-302 bp]GATGTCC[-296 bp]), and transfer of the SRE to a neutral promoter also conferred neuroendocrine selectivity. Expression of both the endogenous gene and the transfected secretogranin II promoter was up-regulated after secretagogues, and the degree of trans-activation of the transfected promoter (2.2- to 5.4-fold) paralleled activation of the endogenous gene (1.8- to 3.2-fold). The 5' promoter deletions revealed complete loss of secretagogue responses after deletion past the CRE. Transfer of the CRE to a neutral promoter conferred secretagogue responses (by 2.2- to 18.6-fold). Substantial (59–74%) falls in secretagogue responses also occurred after deletion past the promoter’s SRE. Transfer of the SRE to a neutral promoter conferred secretagogue responses (by 2.7- to 8.3-fold). We conclude that the CRE is a crucial determinant of cell type-specific constitutive and secretagogue-inducible expression of the secretogranin II gene and that the SRE also plays a substantial role in both processes.

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