Expression and putative role of 14-3-3 proteins in corticotroph tumours

Tang, Sicheng (2022): Expression and putative role of 14-3-3 proteins in corticotroph tumours. Dissertation, LMU München: Medizinische Fakultät

Abstract

Cushing’s disease is caused by ACTH hypersecretion from corticotroph tumours resulting in hypercortisolism. The genetic basis of Cushing’s disease is a single somatic mutational hotspot in the USP8 gene. USP8 mutations are found in around half of Cushing’s disease (corticotroph) tumours, where they potentiate ACTH synthesis. The USP8 mutational hotspot is within a region that binds to 14-3-3 adaptor proteins, which regulate its catalytic activity by facilitating its autoinhibition. 14-3-3 binding is disrupted in USP8 mutants, which subsequently have higher deubiquitinase activity. 14-3-3 proteins are involved in many signalling pathways and are deregulated in several human cancers. However their expression and role in corticotroph tumours has not been examined. The aim of the present thesis was to investigate the expression of USP8-interacting 14-3-3 proteins in human corticotroph tumours and examine their role on corticotroph tumour function and cell viability in an in vitro murine corticotroph tumour cell model. All 14-3-3 proteins were detected at different expression levels, with 14-3-3ε showing the highest expression in corticotroph tumours compared to the normal pituitary. In the Cushing’s patient cohort, high 14-3-3ε expression correlated with lack of invasion, better postoperative outcome, total surgical resection and postoperative remission, as well as, with USP8 mutational status. In contrast, 14-3-3σ expression was significantly lower in corticotroph tumours compared to the normal tissue and no significant correlations with clinical parameters were found. 14-3-3ε overexpression did not affect corticotroph tumour cell viability in vitro, but it increased human POMC promoter activity. Gene enrichment analysis indicated potential 14-3-3ε client proteins and processes that may be involved in this stimulatory POMC regulation. Using small molecule inhibitors against the main 14-3-3ε signaling targets, revealed a role for MEK on 14-3-3ε-induced POMC promoter activity. In conclusion, the present thesis demonstrates aberrant expression of 14-3-3ε in corticotroph tumours, which may affects Cushing’s disease tumour progression and management.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: usp8, 14-3-3 proteins, corticotroph tumours, Cushing's disease
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 28. Juli 2022
• 1. Bericht­erstatter:in: Theodoropoulou, Marily