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Submitted on July 7, 2006
Accepted on August 28, 2006
Division of Endocrinology, Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, California 90048, USA; Department of Internal Medicine II, Klinikum der Ludwig-Maximilians-Universität München, Standort Grosshadern, Munich 81377, Germany
* To whom correspondence should be addressed. E-mail: melmed{at}csmc.edu.
PTTG1, a securin protein, also behaves as a transforming gene and is overexpressed in pituitary tumors. As pituitary folliculostellate (FS) cells regulate pituitary tumor growth factors by paracrine mechanisms, EGF receptor (EGFR)-mediated PTTG1 expression and cell proliferation was tested in pituitary FS TtT/GF cells. EGFR ligands caused up to 3-fold induction of Pttg1 mRNA expression, enhanced PCNA and increased entry of G0/1 arrested cells into S-phase. PTTG binding Factor (PBF) mRNA expression was not altered. EGF-induced Pttg1 expression and cell proliferation was abolished by pre-incubation of TtT/GF cells with EGFR inhibitors AG1478 and gefitinib. PI3K, PKCs, and MAPKs, but not JNK and JAK signaling regulated EGF-induced Pttg1, as well as PCNA mRNA expression, and entry into S-phase. EGF-induced EGFR and ERK1/2 phosphorylation was followed by rapid MEK-dependent activation of Elk-1 and c-Fos. EGF-induced Pttg1 expression peaked at the S-G2 transition and declined thereafter. Pttg1 cell cycle-dependency was confirmed by suppression of EGF-induced Pttg1 mRNA by blockade of cells in early S-phase. The results show that PTTG1 and its binding protein PBF are expressed in pituitary FS TtT/GF cells. EGFR ligands induce PTTG1 and regulate S phase, mediated by PI3K, PKC, and MAPK pathways. PTTG1 is therefore a target for EGFR-mediated paracrine regulation of pituitary cell growth.
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