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v-ras and protein kinase C dedifferentiate thyroid cells by down-regulating nuclear cAMP-dependent protein kinase A
A Gallo1, E Benusiglio, I M Bonapace
1Dipartimento di Biologia e Patologia Molecolare e Cellulare, Universita di Napoli, Italy.
Abstract:
Ras proteins are membrane-associated transducers of eternal stimuli to unknown intracellular targets. The constitutively activated v-ras oncogene induces dedifferentiation in thyroid cells. v-Ras appears to act by stimulating protein kinase C (PKC), which inhibits the nuclear migration of the catalytic subunit of the cAMP-dependent protein kinase A (PKA). Nuclear tissue-specific and housekeeping trans-acting factors that are dependent on phosphorylation by PKA are thus inactivated. Exclusion of the PKA subunit from the nucleus could represent a general mechanism for the pleiotropic effects of Ras and PKC on cellular growth and differentiation.
Insights
Ras proteins, activated by the v-ras oncogene, cause thyroid cell dedifferentiation by stimulating protein kinase C (PKC). This inhibits cAMP-dependent protein kinase A (PKA) nuclear entry, affecting cellular growth and differentiation.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Oncology
Background:
- Ras proteins are key signal transducers linking external stimuli to intracellular responses.
- Aberrant Ras signaling, particularly via the v-ras oncogene, is implicated in cellular dedifferentiation and oncogenesis.
- The precise downstream mechanisms of Ras in cellular differentiation remain incompletely understood.
Purpose of the Study:
- To elucidate the intracellular mechanisms by which the v-ras oncogene induces dedifferentiation in thyroid cells.
- To investigate the role of protein kinase C (PKC) and cAMP-dependent protein kinase A (PKA) in Ras-mediated cellular changes.
- To identify potential nuclear targets regulated by Ras signaling pathways.
Main Methods:
- Utilized the v-ras oncogene in thyroid cell models.
- Investigated the activation and localization of protein kinase C (PKC) and protein kinase A (PKA).
- Analyzed the impact of Ras signaling on nuclear factor phosphorylation and translocation.
Main Results:
- Constitutively activated v-ras oncogene induced thyroid cell dedifferentiation.
- v-Ras signaling stimulated protein kinase C (PKC) activity.
- PKC activation inhibited the nuclear translocation of the catalytic subunit of cAMP-dependent protein kinase A (PKA).
- Nuclear factors dependent on PKA phosphorylation were inactivated due to PKA subunit exclusion from the nucleus.
Conclusions:
- Ras and PKC signaling pathways converge to regulate PKA nuclear localization.
- Exclusion of the PKA catalytic subunit from the nucleus is a potential mechanism for Ras-mediated pleiotropic effects on cell growth and differentiation.
- This pathway inactivation of nuclear factors may underlie the oncogenic effects of Ras in thyroid cells.