title: Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors.
abstract: Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascades are key signalling pathways interacting with each other to regulate cell growth and tumourigenesis. We have previously shown B-Raf and Akt overexpression and/or overactivation in pituitary adenomas. The aim of this study is to assess the expression of their downstream components (MEK1/2, ERK1/2, mTOR, TSC2, p70S6K) and effectors (c-MYC and CYCLIN D1). We studied tissue from 16 non-functioning pituitary adenomas (NFPAs), six GH-omas, six prolactinomas and six ACTH-omas, all collected at transsphenoidal surgery; 16 normal autopsy pituitaries were used as controls. The expression of phospho and total protein was assessed with western immunoblotting, and the mRNA expression with quantitative RT-PCR. The expression of pSer217/221 MEK1/2 and pThr183 ERK1/2 (but not total MEK1/2 or ERK1/2) was significantly higher in all tumour subtypes in comparison to normal pituitaries. There was no difference in the expression of phosphorylated/total mTOR, TSC2 or p70S6K between pituitary adenomas and controls. Neither c-MYC phosphorylation at Ser 62 nor total c-MYC was changed in the tumours. However, c-MYC phosphorylation at Thr58/Ser62 (a response target for Akt) was decreased in all tumour types. CYCLIN D1 expression was higher only in NFPAs. The mRNA expression of MEK1, MEK2, ERK1, ERK2, c-MYC and CCND1 was similar in all groups. Our data indicate that in pituitary adenomas both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways are upregulated in their initial cascade, implicating a pro-proliferative signal derangement upstream to their point of convergence. However, we speculate that other processes, such as senescence, attenuate the changes downstream in these benign tumours.
authors.affiliation: Barts and the London School of Medicine, Centre for Endocrinology, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Dworakowska
authors.forename: E
authors.initials: E
authors.lastname: Wlodek
authors.forename: C A
authors.initials: CA
authors.lastname: Leontiou
authors.forename: S
authors.initials: S
authors.lastname: Igreja
authors.forename: M
authors.initials: M
authors.lastname: Cakir
authors.forename: M
authors.initials: M
authors.lastname: Teng
authors.forename: N
authors.initials: N
authors.lastname: Prodromou
authors.forename: M I
authors.initials: MI
authors.lastname: Góth
authors.forename: S
authors.initials: S
authors.lastname: Grozinsky-Glasberg
authors.forename: M
authors.initials: M
authors.lastname: Gueorguiev
authors.forename: B
authors.initials: B
authors.lastname: Kola
authors.forename: M
authors.initials: M
authors.lastname: Korbonits
authors.forename: A B
authors.initials: AB
authors.lastname: Grossman
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D055815:Young Adult; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019938:Cyclin D1; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; C530104:CCND1 protein, human; C489427:MYC protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human