ECE2021 Oral Communications Oral Communications 8: Pituitary and Neuroendocrinology (6 abstracts)
Expression and putative role of 14–3-3 proteins in corticotroph tumours
Sicheng Tang 1 , Luis Gustavo Perez-Rivas 1 , Adriana Albani 1 , Roman Rotermund 2 , Jörg Flitsch 2 , Jürgen Honegger 3 , Walter Rachinger 4 , Sigrun Röber 5 , Jochen Herms 5 , Martin Reincke 1 & Marily Theodoropoulou 1
1Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Endocrinology, Munich, Germany; 2Klinik für Neurochirurgie, Universitätskrankenhaus Hamburg-Eppendorf, Klinik für Neurochirurgie, Germany; 3University Hospital Tübingen, Department of Neurosurgery, Germany; 4Neurochirurgische Klinik und Poliklinik, Klinikum der LMU München, Neurochirurgische, Germany; 5Center for Neuropathology and Prion Research & Munich Cluster of Systems Neurology, Klinikum der LMU München, Germany
Introduction
Somatic USP8 mutations are found in around 50% of Cushing’s disease tumours and are located in a single mutational hotspot that contains the recognition site for 14–3-3. These proteins bind to phosphoserine recognition motifs to alter the function and location of their target proteins, and are deregulated in several cancers.
Aim
To explore the expression and function of 14–3-3 proteins in corticotroph tumours.
Methods
We analysed the expression of 14–3-3 epsilon (YWHAE), gamma (YWHAG), sigma (SFN) and zeta (YWHAZ) on 16 fresh frozen human corticotroph (8 USP8 wild type, 6 USP8 mutant, 2 unknown) and 3 normal pituitaries by qPCR. We determined 14–3-3 epsilon immunoreactivity on 54 FFPE human corticotroph tumours (23 USP8wt, 31 USP8mut) by immunohistochemistry (H-score). To investigate the possible role of 14–3-3 epsilon on corticotroph physiology, we overexpressed human 14–3-3 epsilon in AtT-20 corticotroph tumour cells and examined its action on human POMC promoter activity. A ligand-binding defective 14–3-3 epsilon mutant (14–3-3 epsilon K49E) that cannot interact with client proteins was used as control.
Results
Transcripts for 14–3-3 epsilon and zeta were 3× and 7× higher in corticotroph tumours compared to normal pituitary (P = 0.04 and P = 0.009 respectively). In contrast we did not detect differences in the expression levels of 14–3-3 gamma and sigma (P = 0.875 and P = 0.21 respectively). 14–3-3 epsilon is the most abundant transcript in corticotroph tumours and its levels are 2.2× higher in USP8mut corticotroph tumours compared to USP8wt (P = 0.006). Cytoplasmic 14–3-3 epsilon immunoreactivity was detected in all but two FFPE corticotroph tumours. Overexpressing human 14–3-3 epsilon in AtT-20 cells significantly increased POMC promoter activity (% increase 234 ± 68, P < 0.05), while the binding defective K49E mutant had no effect.
Conclusions
Corticotroph tumours overexpress 14–3-3 epsilon compared to the normal pituitary, and this expression is higher in USP8mut tumours. 14–3-3 epsilon triggers POMC promoter activity in a yet to be delineated mechanism with potential role to corticotroph pathophysiology.
Volume 73
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Endocrine Abstracts
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