A. Feliciello et al., THE V-KI-RAS ONCOGENE ALTERS CAMP NUCLEAR SIGNALING BY REGULATING THELOCATION AND THE EXPRESSION OF CAMP-DEPENDENT PROTEIN-KINASE II-BETA, The Journal of biological chemistry, 271(41), 1996, pp. 25350-25359
The v-Ki-Ras oncoprotein dedifferentiates thyroid cells and inhibits n
uclear 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, RII beta, translocates from the
membranes to the cytosol. RII beta mRNA and protein were eventually de
pleted. These effects were mimicked by expressing AKAP45, a truncated
version of the RII anchor protein, AKAP75. Because AKAP45 lacks membra
ne targeting domains, it induces the translocation of PKAII to the cyt
oplasm. Expression of AKAP45 markedly decreased thyroglobulin mRNA lev
els and inhibited accumulation of C-PKA in the nucleus. Our results su
ggest that: 1) The localization of PKAII influences cAMP signaling to
the nucleus; 2) Ras alters the localization and the expression of PKAI
I; 3) Translocation of PKAII to the cytoplasm reduces nuclear C-PKA ac
cumulation, resulting in decreased expression of cAMP-dependent genes,
including RII beta, TSH receptor, and thyroglobulin. The loss of RII
beta permanently down-regulates thyroid-specific gene expression.