Oncogene activation in pituitary tumors.
Pituitary tumors constitute 10% of intracranial neoplasms and are mostly benign, monoclonal adenomas derived from single mutant cells. Pituitary oncogenes have been intensively studied and three of them, gsp, ccnd1, and PTTG are abundant in significant numbers of cases. gsp is present in approximately 40% of Caucasian patients with GH-secreting tumors and results from a mutated, constitutively active alpha subunit of Gs protein. Persistent activation of the cAMP-PKA-CREB pathway may lead to uncontrolled cell proliferation and GH secretion. ccnd1 is overexpressed cyclin D1, and cyclin D1 gene is amplified in some pituitary tumors. PTTG is expressed in most pituitary tumors. PTTG is localized to both the nucleus and cytoplasm and interacts with several protein partners. At least three tumorigenesis mechanisms are proposed for human PTTG. 1) PTTG and FGF form a positive feedback loop and stimulate tumor vascularity. 2) PTTG transactivates c-myc or other pro-proliferation genes. 3) PTTG overexpression causes aneuploidy. PTTG expression activates p53 and causes p53-dependent and -independent apoptosis. Due to lack of functional human pituitary cell cultures and appropriate animal models for pituitary tumors, many of the results reviewed here are obtained from heterologous systems.
Yu
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Cedars-Sinai Research Institute-UCLA School of Medicine, Los Angeles, CA 90048, USA.
Melmed
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D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D003001:Cloning, Molecular; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009857:Oncogenes; D009928:Organ Specificity; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D051381:Rats; D064249:Securin; D015398:Signal Transduction; D013045:Species Specificity; D015533:Transcriptional Activation; D014162:Transfection
D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D019938:Cyclin D1; D019205:GTP-Binding Protein alpha Subunits, Gs