Pituitary Gene Signalling Pathway

Abstract

The anterior pituitary contains five trophic hormone‐secreting cells, including adrenocorticotropic hormone (ACTH)‐secreting corticotrophs, luteinising hormone (LH)‐/follicle‐stimulating hormone (FSH)‐secreting gonadotrophs, thyroid‐stimulating hormone (TSH)‐secreting thyrotrophs, growth hormone (GH)‐secreting somatotrophs and prolactin (PRL)‐secreting lactotrophs. Each cell is differentiated from stem cells by intrinsic and extrinsic signals. Pituitary hormone synthesis and secretion is strictly regulated by stimulating hormone, mainly from the hypothalamus, and suppressing hormone, predominantly from peripheral tissues, as a negative feedback system. Pituitary adenomas are the most common pathological state in the anterior pituitary. Several impaired signalling pathways related with pituitary tumourigenesis have been shown in human and animal studies. These include cAMP‐PKA signalling pathway, cell cycle signalling pathway and epigenetic changes. These disruptions could induce not only pituitary cell proliferation but also hormone hypersecretion.

Key Concepts

  • The pituitary gland contains five trophic cells.
  • These cells are differentiated from stem cells by intrinsic and extrinsic signallings.
  • Hormone synthesis and secretion is regulated by stimulatory and inhibitory signallings.
  • Pituitary adenomas are the most common pathological state in the anterior pituitary.
  • Human and animal studies identified several genes related to pituitary adenomas.
  • Impaired cAMP‐PKA and/or cell cycle signalling pathway has an important role in pituitary tumourigenesis.
  • Epigenetic changes deregulate gene signallings related to pituitary tumourigenesis.

Keywords: pituitary gland; transcription factor; pituitary adenomas; cell cycle; cAMP; PKA; epigenome

Figure 1. Schema of cAMP‐PKA signalling pathway related to pituitary tumourigenesis.
Figure 2. Schema of cell cycle signalling pathway related to pituitary tumourigenesis.
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References

Acampora D, Mazan S, Tuorto F, et al. (1998) Transient dwarfism and hypogonadism in mice lacking Otx1 reveal prepubescent stage‐specific control of pituitary levels of GH, FSH and LH. Development 125: 1229–1239.

Bale TL, Picetti R, Contarino A, et al. (2002) Mice deficient for both corticotropin‐releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety‐like behavior. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 22: 193–199.

Beckers A, Aaltonen LA, Daly AF, et al. (2013) Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrine Reviews 34: 239–277.

Ben‐Jonathan N, Chen S, Dunckley JA, et al. (2009) Estrogen receptor‐alpha mediates the epidermal growth factor‐stimulated prolactin expression and release in lactotrophs. Endocrinology 150: 795–802.

Ben‐Shlomo A and Melmed S (2010) Pituitary somatostatin receptor signaling. Trends in Endocrinology and Metabolism 21: 123–133.

Boockfor FR, Hoeffler JP and Frawley LS (1986) Estradiol induces a shift in cultured cells that release prolactin or growth hormone. American Journal of Physiology 250: E103–105.

Cano DA, Soto‐Moreno A and Leal‐Cerro A (2014) Genetically engineered mouse models of pituitary tumors. Frontiers in Oncology 4: 203.

Charles MA, Saunders TL, Wood WM, et al. (2006) Pituitary‐specific Gata2 knockout: effects on gonadotrope and thyrotrope function. Molecular Endocrinology 20: 1366–1377.

Denes J, Swords F, Rattenberry E, et al. (2015) Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. Journal of Clinical Endocrinology and Metabolism 100: E531–541.

Fukuoka H (2015) New potential targets for treatment of Cushing's disease: epithelial growth factor receptor and cyclin‐dependent kinases. Pituitary 18: 274–278.

Fusco A and Fedele M (2007) Roles of HMGA proteins in cancer. Nature Reviews Cancer 7: 899–910.

Giacomini D, Paez‐Pereda M, Stalla J, et al. (2009) Molecular interaction of BMP‐4, TGF‐beta, and estrogens in lactotrophs: impact on the PRL promoter. Molecular Endocrinology 23: 1102–1114.

Gillam MP, Nimbalkar D, Sun L, et al. (2014) MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2. Oncogene 34 (7): 932–938.

Giustina A and Veldhuis JD (1998) Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocrine Reviews 19 (6): 717–797.

Heuser I (1998) Anna‐Monika‐Prize paper. The hypothalamic‐pituitary‐adrenal system in depression. Pharmacopsychiatry 31: 10–13.

Ikeda Y, Lala DS, Luo X, et al. (1993) Characterization of the mouse FTZ‐F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Molecular Endocrinology 7: 852–860.

Jenks BG (2009) Regulation of proopiomelanocortin gene expression: an overview of the signaling cascades, transcription factors, and responsive elements involved. Annals of the New York Academy of Sciences 1163: 17–30.

Kelberman D, Rizzoti K, Lovell‐Badge R, et al. (2009) Genetic regulation of pituitary gland development in human and mouse. Endocrine Reviews 30: 790–829.

Langlois MF, Zanger K, Monden T, et al. (1997) A unique role of the beta‐2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. Mapping of a novel amino‐terminal domain important for ligand‐independent activation. The Journal of Biological Chemistry 272: 24927–24933.

Lania AG, Mantovani G and Spada A (2006) Mechanisms of disease: mutations of G proteins and G‐protein‐coupled receptors in endocrine diseases. Nature Clinical Practice Endocrinology & Metabolism 2: 681–693.

Li XH, Wang EL, Zhou HM, et al. (2014) MicroRNAs in human pituitary adenomas. International Journal of Endocrinology 2014: 435171.

Lin Y, Jiang X, Shen Y, et al. (2009) Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocrine‐Related Cancer 16: 301–310.

Liu JC, Baker RE, Sun C, et al. (2002) Activation of Go‐coupled dopamine D2 receptors inhibits ERK1/ERK2 in pituitary cells. A key step in the transcriptional suppression of the prolactin gene. Journal of Biological Chemistry 277: 35819–35825.

Liu X, Kano M, Araki T, et al. (2015) ErbB receptor‐driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology 156: 71–79.

Lugo DI and Pintar JE (1996) Ontogeny of basal and regulated proopiomelanocortin‐derived peptide secretion from fetal and neonatal pituitary intermediate lobe cells: melanotrophs exhibit transient glucocorticoid responses during development. Developmental Biology 173: 110–118.

Melmed S (2003) Mechanisms for pituitary tumorigenesis: the plastic pituitary. Journal of Clinical Investigation 112: 1603–1618.

Melmed S (2011) Pathogenesis of pituitary tumors. Nature Reviews Endocrinology 7: 257–266.

Murray PG, Higham CE and Clayton PE (2015) 60 years of neuroendocrinology: the hypothalamo‐GH axis: the past 60 years. The Journal of Endocrinology 226: T123–140.

Peverelli E, Mantovani G, Lania AG, et al. (2014) cAMP in the pituitary: an old messenger for multiple signals. Journal of Molecular Endocrinology 52: R67–77.

Poulin G, Lebel M, Chamberland M, et al. (2000) Specific protein‐protein interaction between basic helix‐loop‐helix transcription factors and homeoproteins of the Pitx family. Molecular and Cellular Biology 20: 4826–4837.

Proulx‐Ferland L, Meunier H, Cote J, et al. (1983) Multiple factors involved in the control of ACTH and alpha‐MSH secretion. Journal of Steroid Biochemistry 19: 439–445.

Pulichino AM, Vallette‐Kasic S, Couture C, et al. (2003) Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. Genes & Development 17: 711–716.

Quirk CC, Lozada KL, Keri RA, et al. (2001) A single Pitx1 binding site is essential for activity of the LHbeta promoter in transgenic mice. Molecular Endocrinology 15: 734–746.

Reincke M, Sbiera S, Hayakawa A, et al. (2015) Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature Genetics 47: 31–38.

Schernthaner‐Reiter MH, Trivellin G and Stratakis CA (2015) MEN1, MEN4, and carney complex: pathology and molecular genetics. Neuroendocrinology.

Shupnik MA, Greenspan SL and Ridgway EC (1986) Transcriptional regulation of thyrotropin subunit genes by thyrotropin‐releasing hormone and dopamine in pituitary cell culture. The Journal of Biological Chemistry 261: 12675–12679.

Suszko MI, Lo DJ, Suh H, et al. (2003) Regulation of the rat follicle‐stimulating hormone beta‐subunit promoter by activin. Molecular Endocrinology 17: 318–332.

Thackray VG, McGillivray SM and Mellon PL (2006) Androgens, progestins, and glucocorticoids induce follicle‐stimulating hormone beta‐subunit gene expression at the level of the gonadotrope. Molecular Endocrinology 20: 2062–2079.

Theodoropoulou M, Arzberger T, Gruebler Y, et al. (2004) Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. Journal of Endocrinology 183: 385–394.

Theodoropoulou M, Reincke M, Fassnacht M, et al. (2015) Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. European Journal of Endocrinology 173: M73–M83.

Trivellin G, Daly AF, Faucz FR, et al. (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New England Journal of Medicine 371: 2363–2374.

Tuominen I, Heliovaara E, Raitila A, et al. (2015) AIP inactivation leads to pituitary tumorigenesis through defective Galphai‐cAMP signaling. Oncogene 34: 1174–1184.

Vlotides G, Eigler T and Melmed S (2007) Pituitary tumor‐transforming gene: physiology and implications for tumorigenesis. Endocrine Reviews 28: 165–186.

Wang H, Bauzon F, Ji P, et al. (2010) Skp2 is required for survival of aberrantly proliferating Rb1‐deficient cells and for tumorigenesis in Rb1+/− mice. Nature Genetics 42: 83–88.

Weinstein LS, Yu S, Warner DR, et al. (2001) Endocrine manifestations of stimulatory G protein alpha‐subunit mutations and the role of genomic imprinting. Endocrine Reviews 22: 675–705.

Weintraub BD, Wondisford FE, Farr EA, et al. (1989) Pre‐translational and post‐translational regulation of TSH synthesis in normal and neoplastic thyrotrophs. Hormone Research 32: 22–24.

Yacqub‐Usman K, Richardson A, Duong CV, et al. (2012) The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nature Reviews Endocrinology 8: 486–494.

Yu S, Asa SL and Ezzat S (2002) Fibroblast growth factor receptor 4 is a target for the zinc‐finger transcription factor Ikaros in the pituitary. Molecular Endocrinology 16: 1069–1078.

Zarate S and Seilicovich A (2010) Estrogen receptors and signaling pathways in lactotropes and somatotropes. Neuroendocrinology 92: 215–223.

Zhou Y, Zhang X and Klibanski A (2014) Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma. Molecular and Cellular Endocrinology 386: 16–33.

Further Reading

Ben‐Jonathan N and Hnasko R (2001) Dopamine as a prolactin (PRL) inhibitor. Endocrine Reviews 22: 724–763.

Chahal HS, Chapple JP, Frohman LA, et al. (2010) Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA). Trends in Endocrinology and Metabolism 21: 419–427.

Cooper O, Vlotides G, Fukuoka H, et al. (2011) Expression and function of ErbB receptors and ligands in the pituitary. Endocrine‐Related Cancer 18: R197–211.

Dworakowska D and Grossman AB (2014) The molecular genetics of corticotroph tumours. In: eLS. Chichester: John Wiley & Sons Ltd. http://www.els.net, DOI: 10.1002/9780470015902.a0024906.

Fukuoka H, Cooper O, Ben‐Shlomo A, et al. (2011) EGFR as a therapeutic target for human, canine, and mouse ACTH‐secreting pituitary adenomas. Journal of Clinical Investigation 121: 4712–4721.

Fukuoka H and Takahashi Y (2014) The role of genetic and epigenetic changes in pituitary tumorigenesis. Neurologia Medico‐Chirurgica (Tokyo) 54: 943–957.

Jiang X and Zhang X (2013) The molecular pathogenesis of pituitary adenomas: an update. Endocrinology and Metabolism (Seoul) 28: 245–254.

de Kock L, Sabbaghian N, Plourde F, et al. (2014) Pituitary blastoma: a pathognomonic feature of germ‐line DICER1 mutations. Acta Neuropathologica 128: 111–122.

Lecoq AL, Kamenicky P, Guiochon‐Mantel A, et al. (2015) Genetic mutations in sporadic pituitary adenomas – what to screen for? Nature Reviews Endocrinology 11: 43–54.

Melmed S (2003) Mechanisms for pituitary tumorigenesis: the plastic pituitary. Journal of Clinical Investigation 112: 1603–1618.

Murray RD and Melmed S (2006) The pituitary. In: eLS. Chichester: John Wiley & Sons Ltd. http://www.els.net, DOI: 10.1038/npg.els.0000065.

Musat M, Morris DG, Korbonits M, et al. (2010) Cyclins and their related proteins in pituitary tumourigenesis. Molecular and Cellular Endocrinology 326: 25–29.

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Cooper, Odelia, and Fukuoka, Hidenori(Feb 2016) Pituitary Gene Signalling Pathway. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026355]