Rapid ras-oncogene-mediated transformation maintains steroidogenic differentiation in adrenocortical parenchymal cells

Roskelley, Calvin D.; Auersperg, Nelly

doi:10.1046/j.1432-0436.1995.5920103.x

Cited by 4 publications

(3 citation statements)

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“…PD098059 also reversed the increased cortisol level in pK568MRSV transfected human adrenocortical cells. In our previous study (Wu et al, 2002), we have proved that lovastatin, a pharmacological inhibitor of p21 ras function (Roskelley and Auersperg, 1995), also reversed the increased cortisol level in mutant K-ras stably transfected human adrenocortical cells. Taken together, these proved that the mutant K-ras gene enhanced not only cell proliferation but also steroidogenesis in steroidogenic phenotype cells by activating of Raf-MEK-MAPK signal transduction pathway.…”

Section: Discussionmentioning

confidence: 83%

“…Previous research on regulation of steroidogenesis mostly focused on regulation of elevated hormone secretion caused by ACTH and Angiotensin II (Toaff et al, 1979;Roskelley and Auersperg, 1995). Little is known concerning the association of oncogene with steroidogenesis regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the influence of hormone secretion seems to be more significant than that of cell growth regulation in adrenocortical tumours. In the past, research regarding cholesteroid regulation has often focused on the well known regulation of elevated caused by adrenocorticotropic hormone (ACTH) and Angiotensin II (Fredlund et al, 1975;Roskelley and Auersperg, 1995;Toaff et al, 1979). Little is known concerning the association hormone secretion of oncogenes with secretion regulation.…”

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confidence: 99%

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Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

Chen

et al. 2002

Br J Cancer

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The result of our previous study has shown that the K-ras mutant (pK568MRSV) transfected human adrenocortical cells can significantly increase cortisol production and independently cause cell transformation. The aim of this study is to investigate the effect of the active K-ras oncogene on the cortisol production in normal human adrenocortical cells. First we used isopropyl thiogalactoside to induce the inducible mutant K-ras expression plasmid, pK568MRSV, in the stable transfected human adrenocortical cells. The result showed that the increase of RasGTP levels in transfected cells was time-dependent after isopropyl thiogalactoside induction. Additionally, results from Western blot analysis revealed significant elevation in phosphorylation of c-Raf-1 and Mitogen-activated protein kinase. We also detected the levels of mRNA encoding Cholesterol side-chain cleavage enzyme (P450 SCC ), 17a-Hydroxylase/17,20-lyase (P450 c17 ) and 3b-Hydroxysteroid dehydrogenase (3bHSD) were increased in human adrenocortical cells transfected with mutant K-ras after IPTG treatment. The increase of mRNA amount in P450 scc P450 c17 and 3bHSD and the elevation of cortisol level were inhibited with a pretreatment of PD098059, a specific extracellular signal-regulated kinase inhibitor. In our previous report, we proved that lovastatin, a pharmacological inhibitor of p21 ras function, also reversed the increase of cortisol level in mutant K-ras stably transfected human adrenocortical cells. Taken together, these findings proved that the active mutant Ras enhanced not only cell proliferation but also steroidogenesis in steroidogenic phenotype cells by activating Raf-MEK-MAPK related signal transduction pathway. Therefore, we believe that K-ras mutants influence regulation of steroidogenesis in adrenocortical cells through RAF-MEK-MAPK pathway.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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