Adrenal Tumorigenesis Targeted by the Corticotropin-Regulated Promoter of the Aldo-Keto Reductase AKR1B7 Gene in Transgenic Mice

Sahut‐Barnola, Isabelle; Lefrançois‐Martinez, Anne‐Marie; Jean, C; Veyssière, G.; Martinez, A

doi:10.3109/07435800009048613

Cited by 27 publications

(17 citation statements)

References 10 publications

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“…1A) were able to confer ZF-specific and ACTH-regulated expression to reporter genes in transgenic mice, recapitulating the essential features of the endogenous gene expression in the adrenal gland (42,43). These cis-acting sequences driving the SV40 large T antigen were shown to induce the formation of cortical tumors in two founder transgenic mice (44). The cells from two of these independent tumors, ATC1 and ATC7-L, were propagated for up to 40 passages without crisis, indicating immortalization.…”

Section: Establishment Of Acth-responsive Adrenocortical Cell Lines Fmentioning

confidence: 95%

“…These cell lines were designated ATC1 and ATC7-L for ATC of founder transgenic mice 1 and 7-Left adrenal, respectively (44). ATC cells were cultured on polylysincoated 10-cm tissue culture dishes in a 1:1 mixture of DMEM and Ham's F-12 medium (DMEM-F12) at 37 C in a 5% CO 2 -95% air atmosphere.…”

Section: Establishment and Culture Of Adrenocortical Tumor Cell (Atc)mentioning

confidence: 99%

“…Taking advantage of the promoter for the akr1b7 gene, which is able to target adrenal expression in the ZF in vivo, we developed adrenocortical cell lines derived from simian virus 40 (SV40) large T antigen-induced tumors obtained by targeted tumorigenesis in transgenic mice (42)(43)(44). These cell lines showed a complete and stable ZF phenotype over more than 25 passages.…”

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confidence: 98%

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Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis

Ragazzon¹,

Lefrançois‐Martinez²,

Val³

et al. 2006

Endocrinology

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We established the first adrenocortical tumor cell lines with complete zona fasciculata (ZF) cell phenotype from tumors induced in transgenic mice by large T-antigen of simian virus 40 under the control of the aldose reductase-like akr1b7 gene promoter. Adrenocortical tumor cell lines produced high amounts of corticosterone and were responsive to ACTH. All genes that are supportive for glucocorticoid synthesis including cyp21a1 and cyp11b1 were expressed, and most of them were transiently up-regulated by ACTH at transcriptional level: stimulation culminated after 3-6 h and returned to basal levels after 24 h. Taking advantage of these cells, we have examined the effect of ACTH on DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on X-chromosome, gene 1) and SF-1 (steroidogenic factor 1), two transcription factors known to respectively repress and activate adrenocortical steroidogenesis by acting on common target genes. According to their antagonistic activities, DAX-1 mRNA and protein levels were transiently down-regulated by ACTH, whereas those of SF-1 were stimulated, with kinetics paralleling those of steroidogenic genes expression, notably of two known SF-1 target genes, star and akr1b7. This suggests an essential role of SF-1/DAX-1 proteins ratio to achieve proper ACTH control of steroidogenic gene expression in cells derived from ZF. This was confirmed in mice adrenals, where repression of dax-1 gene and concomitant up-regulation of sf-1, star, and akr1b7 genes were observed in response to ACTH stimulation. In conclusion, using both unique differentiated cell lines and in vivo approaches, we provide the first evidence that hormonally induced changes in SF-1/DAX-1 ratio are part of the molecular arsenal of ZF cells to fine tune ACTH responsiveness.

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Section: Establishment Of Acth-responsive Adrenocortical Cell Lines Fmentioning

confidence: 95%

Section: Establishment and Culture Of Adrenocortical Tumor Cell (Atc)mentioning

confidence: 99%

mentioning

confidence: 98%

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Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis

Ragazzon¹,

Lefrançois‐Martinez²,

Val³

et al. 2006

Endocrinology

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“…Promotors that have been used to target the adrenal cortex include 5'-flanking sequences from the human CYP11A gene (Compagnone et al, 1997), the aldose reductase-like (akr1b7) gene (Sahut-Barnola et al, 2000), and the inhibin-α promotor (Kananen et al, 1996). In particular, the inhibin-α promotor driven transgenic animal (inhα/Tag) has been phenotypically characterized in great detail and a large body of literature demonstrates the gonadectomy-dependent induction of adrenocortical tumorigenesis (Kananen et al, 1997;Rilianawati et al, 2000;Rilianawati et al, 1998).…”

Section: Genetically Modified Mouse Models With Actsmentioning

confidence: 99%

Animal Models of Adrenocortical Tumorigenesis

Galac

Wilson

2015

Endocrinology and Metabolism Clinics of North America

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Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species -mouse, ferret, and dog -are reviewed, and their relevance to adrenocortical tumors in humans is discussed.

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“…These include isocaproic aldehyde, derived from the cholesterol side chain discarded by the action of CYP11A, and free radicals that may be generated by 'leaky' P450s. It has been suggested that enzymes such as the aldose reductase-like AKR1B7 and MnSOD may be present in steroidogenic tissues for this reason (Sahut-Barnola et al 2000, Suwa et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Manganese superoxide dismutase activity in the rat adrenal

Raza¹,

Okamoto²,

Takemori³

et al. 2005

Journal of Endocrinology

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In the light of studies suggesting that transcription of the gene coding for manganese superoxide dismutase (MnSOD) is induced by ACTH in the rat adrenal gland, northern blot analysis was used to determine its mRNA distribution. It was found that mRNA coding for MnSOD is primarily present in the inner zones of the rat adrenal cortex, and not the glomerulosa. To investigate the functional relationships between MnSOD activity and expression and adrenocortical function, adrenals and blood were taken from animals pretreated with corticotrophin or betamethasone (Betnesol), or subjected to a low-sodium diet. MnSOD activity in inner zone mitochondrial fractions was enhanced by corticotrophin and by a low-sodium diet, but suppressed by betamethasone. Apparent cytosolic MnSOD activity, total cytosolic MnSOD and CuZnMn-SOD, and glomerulosa mitochondrial MnSOD all were unaffected. Steroid assays showed a clear correlation between circulating corticosterone and inner zone mitochondrial MnSOD, but none between aldosterone and glomerulosa MnSOD.Immunoblot analysis of MnSOD showed two apparent isoforms, at approximately 25 kDa and 75 kDa. There was a partial relationship between expression of the 75 kDa isoform and MnSOD activity, in that it was induced by corticotrophin. However, there was also a slight induction with betamethasone, and a low-sodium diet had no effect. The 25 kDa MnSOD isoform was unaffected by the treatments. The results suggest that MnSOD may have a specific role in the steroidogenic function of the fasciculata/reticularis of the rat adrenal, but not in that of the glomerulosa.

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Adrenal Tumorigenesis Targeted by the Corticotropin-Regulated Promoter of the Aldo-Keto Reductase AKR1B7 Gene in Transgenic Mice

Cited by 27 publications

References 10 publications

Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis

Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis

Animal Models of Adrenocortical Tumorigenesis

Manganese superoxide dismutase activity in the rat adrenal

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