Ki-ras oncogene interferes with the expression of cyclic AMP-dependent promoters.
The expression of thyroglobulin and other thyroid-specific markers depends upon the activation of protein kinase A (PKA) by cyclic AMP. A rat thyroid cell line dedifferentiates when transformed with Ki-ras oncogene. The decrease in thyroglobulin gene expression parallels a reduction in the level of PKA nuclear catalytic subunit. We find that the activity of cAMP-responsive elements and thyroglobulin promoters is down-regulated in Ras-transformed cells. Transcription of a third cAMP-regulated gene, H-ferritin, is similarly reduced. cAMP-responsive element and H-ferritin expression were stimulated when intracellular cAMP levels were increased. Reactivation of the thyroglobulin promoter required depletion of PKC in addition to increased cAMP. We also find that v-Ras activation leads to a significant increase in membrane-bound PKC. These data support the idea that v-Ras via PKC inhibits the transmission of cAMP-PKA signals to the nucleus. We suggest that the thyroglobulin promoter is more sensitive than other cAMP-dependent promoters to reduced nuclear levels of PKA catalytic subunit.
Gallo
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A
Dipartimento di Biologia e Patologia Molecolare e Cellulare, II Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, Italy.
Feliciello
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Varrone
A
A
Cerillo
R
R
Gottesman
M E
ME
Avvedimento
V E
VE
D000818:Animals; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D005293:Ferritins / Q000235:genetics; D005786:Gene Expression Regulation; D011905:Genes, ras; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013954:Thyroglobulin / Q000235:genetics*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D014162:Transfection / Q000235:genetics
D012333:RNA, Messenger; D005293:Ferritins; D013954:Thyroglobulin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C