Vanin-1 inactivation antagonizes the development of adrenocortical neoplasia in Sf-1 transgenic mice.
SF-1 (NR5A1) overexpression can induce adrenocortical tumor formation in transgenic mice and is associated with more severe prognosis in patients with adrenocortical cancer. In this study we have identified Vanin-1 (Vnn1), a SF-1 target gene, as a novel modulator of the tumorigenic effect of Sf-1 overexpression in the adrenal cortex. Vanin-1 is endowed with pantetheinase activity, releasing cysteamine in tissues and regulating cell response to oxidative stress by modulating the production of glutathione. Sf-1 transgenic mice developed adrenocortical neoplastic lesions (both dysplastic and nodular) with a frequency increasing with age. Genetic ablation of the Vnn1 gene in Sf-1 transgenic mice significantly reduced the severity of neoplastic lesions in the adrenal cortex. This effect could be reversed by treatment of Sf-1 transgenic/Vnn1 null mice with cysteamine. These data show that alteration of the mechanisms controlling intracellular redox and detoxification mechanisms is relevant to the pathogenesis of adrenocortical neoplasia induced by SF-1 overexpression.
Institut de Pharmacologie Moléculaire et Cellulaire CNRS (P.L.D.L., A.E.W., M.J., E.L.) Valbonne 06560, France; Associated International Laboratory for the Study of the ALterations of Gene Expression in Childhood Cancers CNRS (P.L.D.L., A.E.W., M.J., E.L.), Valbonne 06560, France; Université de Nice-Sophia Antipolis (P.L.D.L., A.E.W., M.J., E.L.), Valbonne 06560, France; Department of Pathology (R.R.K.), Erasmus MC-University Medical Center, Rotterdam 3015, The Netherlands; Department of Molecular and Integrative Physiology (L.L.H.), University of Kansas Medical Center, Kansas City, Kansas 66160; Centre d'Immunologie de Marseille-Luminy (P.N.), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (P.N.), U1104, Marseille, France; and Centre National de la Recherche Scientifique (P.N.), UMR7280, Marseille, France.
Perle
P
Latre de Late
Abeer
A
El Wakil
Marielle
M
Jarjat
Ronald R
RR
de Krijger
Leslie L
LL
Heckert
Philippe
P
Naquet
Enzo
E
Lalli
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003543:Cysteamine / Q000378:metabolism / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006965:Hyperplasia; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D058851:GPI-Linked Proteins; D017382:Reactive Oxygen Species; D054339:Steroidogenic Factor 1; D003543:Cysteamine; D000581:Amidohydrolases; C022314:pantetheinase; D005978:Glutathione