Mechanisms for Growth Factor-Induced Pituitary Tumor Transforming Gene-1 Expression in Pituitary Folliculostellate TtT/GF Cells

Abstract

PTTG1, a securin protein, also behaves as a transforming gene and is overexpressed in pituitary tumors. Because pituitary folliculostellate (FS) cells regulate pituitary tumor growth factors by paracrine mechanisms, epidermal growth factor (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 proliferating cell nuclear antigen, and increased entry of G0/1-arrested cells into S-phase. PTTG binding factor mRNA expression was not altered. EGF-induced Pttg1 expression and cell proliferation was abolished by preincubation of TtT/GF cells with EGFR inhibitors AG1478 and gefitinib. Phosphatidylinositol 3 kinase, protein kinase C, and MAPK, but not c-Jun N-terminal kinase and Janus activating kinase signaling regulated EGF-induced Pttg1, as well as proliferating cell nuclear antigen mRNA expression and entry into S-phase. EGF-induced EGFR and ERK1/2 phosphorylation was followed by rapid MAPK kinase/ERK kinase-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 PTTG binding factor are expressed in pituitary FS TtT/GF cells. EGFR ligands induce PTTG1 and regulate S-phase, mediated by phosphatidylinositol 3 kinase, protein kinase C, and MAPK pathways. PTTG1 is therefore a target for EGFR-mediated paracrine regulation of pituitary cell growth.

Regulation of Pituitary Tumor Transforming Gene (PTTG) Expression and Phosphorylation in Thyroid Cells

“…The observation of reduced hPTTG after SP1 depletion confirmed its role in hPTTG transcription, consistent with siRNA studies in hepatocellular carcinoma cells (63). After SP1 knockdown, hPTTG was nonetheless inducible by growth factors, suggesting the effect was independent of SP1, concurrent with studies of hPTTG regulation by EGF in pituitary folliculostellate TtT/GF cells (29).…”

“…Although hormones such as estrogen (24,25), TSH (4), and insulin (26,27) have been implicated in regulation of hPTTG expression, there is increasing evidence that hPTTG expression is in turn regulated by growth factors. hPTTG was induced by epidermal growth factor (EGF) and TGF␣ in U87 human glioma cells (28) and in pituitary folliculostellate TtT/GF cells via MAPK and phosphoinositide 3-kinase (PI3K) pathways (29). The same pathways were also implicated in upregulation of hPTTG by IGF-1 in human breast cancer cells and malignant astrocytes (26,27).…”

Pituitary Tumor Transforming Gene 1 Induces Tumor Necrosis Factor-α Production from Keratinocytes: Implication for Involvement in the Pathophysiology of Psoriasis

“…PTTG1 had a positive effect on keratinocyte proliferation (Ishitsuka et al, 2012), and PTTG1 expression was induced by the EGFR-mediated proliferation signal as demonstrated in earlier studies (Vlotides et al, 2006;Vlotides et al, 2008). Moreover, we confirmed increased secretion of EGF from cultured NHKs overexpressing PTTG1 by ELISA (data not shown).…”

Key signaling molecules in pituitary tumors

“…EGF, which is known to act directly on hormone-secreting pituitary cells, is shown to affect cell proliferation and PTTG1 expression in hormonally inactive FS cells, the major source of pituitary cytokines and growth factors [64]. Pituitary adenomas could benefit from inhibition of EGFR-mediated PTTG1 expression in FS cells by intracellular blockade of paracrine signaling [65].…”

“…Pituitary adenoma therapy could benefit from inhibition of EGFR-mediated PTTG1 expression in FS cells by intracellular blockade of paracrine signaling [65]. Highly expressed in secretory pituitary adenoma -GH, PRL, TSH [77] Review Key signaling molecules in pituitary tumors Gene therapy techniques specifically targeting endogenous PTTG1 expression in tumors may serve as a useful investigative therapeutic tool [23].…”