Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation

Abstract

HIGHLIGHTSd b-catenin activation drives adrenal hyperplasia by blocking cellular differentiation d Upregulation of Pde2a, an inhibitor of cAMP/PKA, is a potential mechanism for the block d Hyperplasia is exacerbated by trophic factor stimulation leading to organomegaly

Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice

“…3g ). Consistent with recent reports [ 30 , 35 ], BCre AS/+ mice exhibited mildly elevated levels of plasma aldosterone in older mice. No difference in corticosterone levels was observed in BCre AS/+ or PCre AS/+ mice compared with controls (Fig.…”

“…Histological and morphological analyses of BCre AS/+ mice demonstrated progressive expansion of the zG at 1 ( n = 8) and 3 ( n = 6) months of age, with a corresponding expansion of the β-catenin + domain (Fig. 2a , S1a ), consistent with our recent report [ 30 ]. Furthermore, these changes were accompanied by an increase in the expression of Wnt/β-catenin target genes Axin2 and Lef1 [ 13 ] (Fig.…”

“…The p53/Rb pathway is composed of proteins that control cell cycle entry at G1 and dysregulation of these molecules is thought to lead to uncontrolled cell proliferation in ACC [ 43 , 44 ]. On the other hand, alterations in proteins of the Wnt/β-catenin-signaling pathway cause aberrant Wnt activation and affect adrenocortical cell renewal, differentiation, and proliferation [ 12 , 14 , 30 ]. Interestingly, the combination of mutations affecting both TP53 and CTNNB1 have been described in a small group of both pediatric and adult patients presenting with malignant adrenocortical tumors and correlates with poor prognosis [ 6 , 9 , 10 , 45 , 46 ], though, in general, the majority of high-risk patients do not simultaneously harbor mutations in both genes [ 47 ].…”

Transcription factors β-catenin and Hex in postnatal development of the rat adrenal cortex: implication in proliferation control

“…In mice subcapsular and glomerulosa cells represent a source for cell renewal. These cells provide maintenance of cell homeostasis in inner layers of the adrenal cortex by proliferation and transdifferentiation [ 18 , 19 ]. Unlike mice rat adrenal cortex has well distinguishable ZG and ZF separated by some layers of undifferentiated cells called zona intermedia.…”

“…Moreover, it should be noted that the most investigations were performed on mice adrenals or mice adrenocortical cell lines while transcriptional regulation of rat adrenal morphogenesis and function are significantly less studied. It is noteworthy, that most experiments on modulation of Wnt signaling in the adrenal cortex were performed on genetically engineered animals and on gain-of-function and loss-of-function models [ 16 , 17 , 18 ]. It significantly complicates evaluation of Wnt signaling function in wild-type laboratory animals, since transcriptional regulation represents a network of cooperating factors, and impaired function of one regulator may change activity of other factors.…”