title: Enhanced protein kinase B/Akt signalling in pituitary tumours.
abstract: Pituitary tumours have previously been shown to harbour several abnormalities that cause deregulation of the cell cycle, particularly down-regulation of expression of the cyclin-dependent kinase inhibitor p27. However, it has been unclear whether these are the primary initiating events, or are secondary to other more proximate alterations in signalling pathways. In other cellular systems the Akt signalling pathway has been associated with downstream modulation of cell-cycle control. The aim of the present study was to test the hypothesis that Akt signalling is enhanced in pituitary tumours, and to see if changes in Akt expression are related to previous findings on low expression levels of the nuclear cell-cycle inhibitor p27 in pituitary tumours. We examined normal and adenomatous human pituitary tissue for mRNA and protein expression of Akt1, Akt2 and p27, and the activation of Akt, as well the phosphatase involved in the inactivation of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). In pituitary adenomas Akt1 and Akt2 mRNA were found to be over-expressed compared with normal pituitary, while PTEN transcripts showed similar levels between the two tissue types. Immunohistochemical expression of phospho-Akt was found to be higher in the tumours than normal pituitaries, while the protein expression of nuclear p27 and PTEN was lower in the adenomas. However, the expression of p27 and Akt were not directly correlated. PTEN sequencing revealed no mutation in the coding region of the gene in pituitary adenomas, and thus we did not locate a cause for the increased phosphorylation of Akt. In summary, we have shown over-expression and activation of the Akt pathway in pituitary tumours, and we speculate that cell-cycle changes observed in such tumours are secondary to these more proximate alterations. Since Akt is a major downstream signalling molecule of growth factor-liganded tyrosine kinase receptors, our data are most compatible with an abnormality at this level as the primary driver of pituitary tumorigenesis.
authors.affiliation: Department of Endocrinology, St Bartholomew's Hospital, London EC1A 7BE, UK.
authors.forename: M
authors.initials: M
authors.lastname: Musat
authors.forename: M
authors.initials: M
authors.lastname: Korbonits
authors.forename: B
authors.initials: B
authors.lastname: Kola
authors.forename: N
authors.initials: N
authors.lastname: Borboli
authors.forename: M R
authors.initials: MR
authors.lastname: Hanson
authors.forename: A M
authors.initials: AM
authors.lastname: Nanzer
authors.forename: J
authors.initials: J
authors.lastname: Grigson
authors.forename: S
authors.initials: S
authors.lastname: Jordan
authors.forename: D G
authors.initials: DG
authors.lastname: Morris
authors.forename: M
authors.initials: M
authors.lastname: Gueorguiev
authors.forename: M
authors.initials: M
authors.lastname: Coculescu
authors.forename: S
authors.initials: S
authors.lastname: Basu
authors.forename: A B
authors.initials: AB
authors.lastname: Grossman
mesh_terms: D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human