Cullin 3 targets the tumor suppressor gene ARMC5 for ubiquitination and degradation

Author:

Cavalcante Isadora Pontes1,Vaczlavik Anna1,Drougat Ludivine1,Lotfi Claudimara Ferini Pacicco2,Perlemoine Karine1,Ribes Christopher1,Rizk-Rabin Marthe1,Clauser Eric3,Fragoso Maria Candida Barisson Villares4,Bertherat Jérôme15,Ragazzon Bruno1

Affiliation:

1. 1Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

2. 2Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

3. 3Université de Paris, PARCC, INSERM, Paris, France

4. 4Adrenal Unit, Hormone and Molecular Genetic Laboratory/LIM42, Hospital of Clinics, School of Medicine, University of São Paulo, São Paulo, Brazil

5. 5Department of Endocrinology, APHP, Cochin Hospital, Paris, France

Abstract

ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.

Publisher

Bioscientifica

Subject

Cancer Research,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism

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