Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans

Gualtieri, Angelica; Kyprianou, Nikolina; Gregory, Louise; Vignola, Maria Lillina; Nicholson, James; Tan, Rachael; Inoue, Shinichi; Scagliotti, Valeria; Casado, Pedro; Blackburn, James; Abollo-Jiménez, Fernando; Marinelli, Eugenia; Besser, Rachel E J; Högler, Wolfgang; Temple, I. Karen; Davies, Justin H; Gagunashvili, Andrey; Robinson, Iain C. A. F.; Camper, Sally A.; Davis, Shannon W.; Cutillas, Pedro R.; Gevers, Evelien; Aoki, Yoko; Dattani, Mehul; Gaston‐Massuet, Carles

doi:10.1038/s41467-021-21712-4

Cited by 14 publications

(14 citation statements)

References 86 publications

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“…Activation of the MAPK pathway by B-Raf V600E , or B-Raf Q241R , leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the B-Raf V600E in embryonic pituitary progenitors promotes expression of cell cycle inhibitors, cell growth arrest, and apoptosis, but not cancer ( 118 ). B-Raf V600E is also a common strong driver of cancer.…”

Section: Developmental Disorders May or May Not Involve The Same Mutations As Cancermentioning

confidence: 99%

How can same-gene mutations promote both cancer and developmental disorders?

2022

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Section: Developmental Disorders May or May Not Involve The Same Mutations As Cancermentioning

confidence: 99%

How can same-gene mutations promote both cancer and developmental disorders?

2022

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“…After transsphenoidal resection, tumor was washed with PBS (pH 7.4) and cells were dispersed using 2.5% Trypsin, Gibco, USA and mechanical dispersion procedure. Cell culture was performed in Dulbecco Modified Eagle Media (DMEM, Gibco, USA) containing fetal calf serum (FCS, Gibco, USA), penicillin and streptomycin at 37 °C and 5% CO2.For immunofluorescence cells, were incubated with primary antibodies [anti-phospho β-catenin Ser552 (# 9566) (1:300), and anti-CD44 (ab157107) (1:100)] as described in [ 28 , 29 ]. After washing, cells were incubated with fluorochrome conjugated secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of β-catenin at Serine552 correlates with invasion and recurrence of non-functioning pituitary neuroendocrine tumours

Rai

Yelamanchi

Radotra

et al. 2022

acta neuropathol commun

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Non-functioning pituitary tumours (NF-PitNETs) are common intracranial benign neoplasms that can exhibit aggressive behaviour by invading neighbouring structures and, in some cases, have multiple recurrences. Despite resulting in severe co-morbidities, no predictive biomarkers of recurrence have been identified for NF-PitNETs. In this study we have used high-throughput mass spectrometry-based analysis to examine the phosphorylation pattern of different subsets of NF-PitNETs. Based on histopathological, radiological, surgical and clinical features, we have grouped NF-PitNETs into non-invasive, invasive, and recurrent disease groups. Tumour recurrence was determined based on regular clinical and radiological data of patients for a mean follow-up of 10 years (SD ± 5.4 years). Phosphoproteomic analyses identified a unique phosphopeptide enrichment pattern which correlates with disease recurrence. Candidate phosphorylated proteins were validated in a large cohort of NF-PitNET patients by western blot and immunohistochemistry. We identified a cluster of 22 phosphopeptides upregulated in recurrent NF-PitNETs compared to non-invasive and invasive subgroups. We reveal significant phosphorylation of the β-catenin at Ser552 in recurrent and invasive NF-PitNETs, compared to non-invasive/non-recurrent NF-PitNET subgroup. Moreover, β-catenin pSer552 correlates with the recurrence free survival among 200 patients with NF-PitNET. Together, our results suggest that the phosphorylation status of β-catenin at Ser552 could act as potential biomarker of tumour recurrence in NF-PitNETs. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-022-01441-5.

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“…Over the last decade, with increasing knowledge of molecular biological mechanisms, we have gathered more insight into the possible mechanisms underlying disturbances in growth hormone secretion, growth hormone resistance and growth plate disturbances. It has been shown that hypothalamic–pituitary genes of the RAS-MAP kinase pathway are involved in the development of the hypothalamic–pituitary axis [ 21 ], which suggests that the hypothalamic–pituitary architecture could be deranged in RASopathies. The previously reported neurosecretory deficiency could be explained by these changes in hypothalamic–pituitary morphology.…”

Section: Endocrine Featuresmentioning

confidence: 99%

Growth, Endocrine Features, and Growth Hormone Treatment in Noonan Syndrome

Dahlgren

Noordam

2022

JCM

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Noonan syndrome is a heterogeneous congenital disorder. The main features are typical facial features, short stature and cardiac defects. The diagnosis is clinical: in 80% of patients with Noonan syndrome a genetic defect can be shown. Inheritance is predominantly autosomal dominant and seldom autosomal recessive. In 2001, PTPN11 was the first gene connected to Noonan syndrome, and until now, at least 20 other genes have been discovered. All genes code for proteins involved in the RAS-MAP-kinase pathway, and therefore, Noonan syndrome is one of the known RASopathies. Other RASopathies include neurofibromatosis and CFC syndrome. Short stature is one of the defining features of Noonan syndrome. The cause is not fully understood but is multifactorial. Other endocrinological features are confined to delayed puberty and hypogonadism in boys and males. To increase adult height, children with Noonan syndrome have been treated with human growth hormone since the 1990s. This seems to be beneficial in most of the children treated. In this narrative review, we describe the current knowledge on growth, endocrinological features and growth hormone treatment in patients with Noonan syndrome.

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Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans

Cited by 14 publications

References 86 publications

How can same-gene mutations promote both cancer and developmental disorders?

How can same-gene mutations promote both cancer and developmental disorders?

Phosphorylation of β-catenin at Serine552 correlates with invasion and recurrence of non-functioning pituitary neuroendocrine tumours

Growth, Endocrine Features, and Growth Hormone Treatment in Noonan Syndrome

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