A mutation and expression analysis of the oncogene <i>BRAF</i> in pituitary adenomas

Ewing, Iain; Pedder-Smith, Stephen; Franchi, Gian Gabriele; Ruscica, Massimiliano; Emery, Michelle; Vax, Vladimir; García, Edwin; Czirják, Sándor; Hanzély, Zoltán; Kola, Blerina; Korbonits, Márta; Grossman, Ashley

doi:10.1111/j.1365-2265.2006.02735.x

Cited by 60 publications

(42 citation statements)

References 30 publications

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“…In fact, in pituitary adenomas, it has been reported that the PI3K/Akt pathway was activated and the ratio of phosphorylated MAPK/ERK was increased (38). Therefore, it is speculated that octreotide regulates a common pathway for PI3K/Akt and MAPK and shows antitumor effects.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue

Horiguchi¹,

Yamada²,

Satoh³

et al. 2009

Clinical Cancer Research

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Purpose: Mixed lineage leukemia (MLL) is a histone methyltransferase that activates gene transcription and associates with menin. In multiple endocrine neoplasia type 1 (Men1), a mutation of menin caused decreased expression of the p27Kip1 and p18 Ink4C genes and deregulated cell growth.We hypothesized that the same pathway might be involved in sporadic pituitary adenomas. Experimental Design: mRNA levels for MLL, Men1, p27 Kip1 , and p18Ink4C were measured in specimens of several sporadic pituitary adenomas, and a search for clinical parameters revealed that octreotide treatment affected the level of expression of some genes tested. To study molecular mechanisms, we cloned and characterized the MLL promoter region and used small interfering RNA for MLL and specific inhibitors for signal transduction pathways.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue

Horiguchi¹,

Yamada²,

Satoh³

et al. 2009

Clinical Cancer Research

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“…A mutation was identified in codon 12 of the HRAS gene (Gly to Val) in a recurrent prolactinoma that was highly invasive and ultimately proved to be fatal (Karga et al, 1992). Overexpression of both BRAF mRNA and protein has also been reported in non-functioning pituitary adenomas (Ewing et al, 2007). Persistent MAPK/ERK pathway activation, by expressing oncogenic KRAS-G12V, promotes differentiation of the bi-hormonal somatolactotroph GH4 precursor cell line into a prolactin-secreting cell type but is not sufficient to drive tumourigenesis (Booth et al, 2014).…”

Section: Hesx1mentioning

confidence: 99%

MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma

et al. 2017

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Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here, we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2 + stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2 + cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a crucial function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2 + cells and suggest that persistent proliferative capacity of Sox2 + cells may underlie the pathogenesis of PCP.

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“…These have been shown to be overactive in many human tumours (Adjei & Hidalgo 2005, Roberts & Der 2007. It has been reported that Akt is overexpressed and overactivated in non-functioning pituitary adenomas (NFPAs; Musat et al 2005), and there is recent evidence that B-Raf, an upstream regulator of the MAPK cascade, is also overexpressed predominantly in NFPAs (Ewing et al 2007). Such activation may account for the changes in cell-cycle components which are a frequent characteristic of pituitary tumours, especially p27 (Lloyd et al 1997, Lidhar et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors

Dworakowska¹,

Wlodek²,

Leontiou³

et al. 2009

Endocrine-Related Cancer

126

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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.

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A mutation and expression analysis of the oncogene BRAF in pituitary adenomas

Cited by 60 publications

References 30 publications

Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue

Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue

MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma

Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors

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