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¹ Department of Physiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan² Department of Physiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China

(Correspondence should be addressed to J Arita; Email: jarita{at}yamanashi.ac.jp)

Adenoviruses are powerful, widely utilized vectors for gene transfer. Limitations to their application, however, have not been well described. We used rat pituitary lactotrophs in primary culture as a model for studying how adenovirus vector infection modulates mitogen-induced proliferation and the activities of mitogen signaling pathways. Infection with adenovirus vectors expressing β-galactosidase (βgal) raised basal proliferative levels and blocked fetal bovine serum (FBS)-induced proliferation of lactotrophs, but did not influence the changes in proliferation induced by forskolin, IGF-I, and bromocriptine. The βgal-expressing adenoviruses did not alter the inhibitory action of 17β-estradiol (E₂) in the presence of IGF-I; however, they blocked the stimulatory action of E₂ in the presence of dextran-coated charcoal-striped serum or forskolin. An adenovirus expressing no protein failed to block FBS-induced proliferation, but was effective in modulating basal proliferative levels and the stimulatory actions of E₂. The increased basal proliferative level and the blockade of FBS-induced proliferation were transient, and lost 5 days after infection while the blockade of the stimulatory action of E₂ in the presence of forskolin persisted. Adenovirus infection raised basal protein levels of the phosphorylated forms of cAMP response element-binding protein (pCREB) and ERK1/2 and increased the proportion of pCREB-immunoreactive lactotrophs. Adenoviruses also altered estrogen-induced responses in mRNA expression of several estrogen-responsive genes in a gene-specific manner. The results demonstrate that an adenovirus vector differentially interferes with lactotroph proliferation in response to various mitogens. Our results suggest that the effects of the adenovirus that are independent of the genes transferred must be considered when performing adenoviral gene transfer in the primary cultures of normal cells.