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Ras oncoprotein disrupts the TSH/CREB signaling upstream adenylyl cyclase in human thyroid cell

Marcella Salzano1, Eleonora Russo, Salvatore Salzano

  • 1Department of Medicine and Surgery, University of Salerno, Baronissi 84081, Salerno, Italy; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.

Journal of Cellular Physiology
|May 14, 2014
PubMed

Insights

Ras oncoprotein disrupts the thyroid-stimulating hormone (TSH)/cAMP response element-binding protein (CREB) pathway in human thyroid cells. This disruption occurs upstream of adenylyl cyclase, indicating cell-specific mechanisms of Ras and cAMP pathway interaction.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Activating RAS gene mutations and p21 Ras oncoprotein overactivation are prevalent in human tumors.
  • p21 Ras oncoproteins dysregulate signaling pathways, leading to thyroid cell dedifferentiation and reduced expression of thyroid-specific genes.

Purpose of the Study:

  • To investigate how the TSH/CREB pathway is modulated by Ras oncoprotein in a human thyroid cell line, given cell-dependent differences observed in other models.
  • To elucidate the specific mechanisms of Ras oncoprotein interaction with the cAMP signaling pathway in human thyroid cells.

Main Methods:

  • Utilized the human thyroid cell line TAD-2.
  • Expressed Ras(V12) oncoprotein in TAD-2 cells.
  • Stimulated CREB phosphorylation using TSH and forskolin.
  • Assessed the effects of Ras(V12) expression and phosphodiesterase inhibition (IBMX) on TSH- and forskolin-stimulated CREB phosphorylation.

Main Results:

  • TSH and forskolin effectively stimulated CREB phosphorylation in TAD-2 cells.
  • Ras(V12) expression inhibited TSH-stimulated CREB phosphorylation but did not affect forskolin-stimulated phosphorylation.
  • Phosphodiesterase inhibition enhanced TSH-stimulated CREB phosphorylation but failed to reverse Ras(V12)-induced inhibition.

Conclusions:

  • Ras oncoprotein disrupts the TSH/CREB pathway upstream of adenylyl cyclase in human thyroid cells.
  • The interaction mechanisms between Ras and the cAMP pathway differ between human and rat thyroid cells.
  • These findings highlight cell-specific regulation of signaling pathways by Ras oncoproteins.

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