The v-Ki-Ras oncogene alters cAMP nuclear signaling by regulating the location and the expression of cAMP-dependent protein kinase IIβ

A. Feliciello, P. Giuliano, A. Porcellini, C. Garbi, S. Obici, E. Mele, E. Angotti, D. Grieco, G. Amabile, S. Cassano, Y. Li, Anna M. Musti, Charles S. Rubin, Max E. Gottesman, Enrico V. Avvedimento

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

The v-Ki-Ras oncoprotein dedifferentiates thyroid cells and inhibits nuclear accumulation of the catalytic subunit of cAMP-dependent protein kinase. After activation of v-Ras or protein kinase C, the regulatory subunit of type II protein kinase A, RIIβ, translocates from the membranes to the cytosol. RIIβ mRNA and protein were eventually depleted. These effects were mimicked by expressing AKAP45, a truncated version of the RII anchor protein, AKAP75. Because AKAP45 lacks membrane targeting domains, it induces the translocation of PKAII to the cytoplasm. Expression of AKAP45 markedly decreased thyroglobulin mRNA levels and inhibited accumulation of C-PKA in the nucleus. Our results suggest that: 1) The localization of PKAII influences cAMP signaling to the nucleus; 2) Ras alters the localization and the expression of PKAII; 3) Translocation of PKAII to the cytoplasm reduces nuclear C-PKA accumulation, resulting in decreased expression of cAMP- dependent genes, including RIIβ, TSH receptor, and thyroglobulin. The loss of RIIβ permanently down-regulates thyroid-specific gene expression.

Original languageEnglish (US)
Pages (from-to)25350-25359
Number of pages10
JournalJournal of Biological Chemistry
Volume271
Issue number41
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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