RhoA activation promotes transformation and loss of thyroid cell differentiation interfering with thyroid transcription factor-1 activity.

  • Medina D
  • Rivas M
  • Cruz P
 et al. 
  • 7


    Mendeley users who have this article in their library.
  • 5


    Citations of this article.


Highly specialized cells, the thyrocytes, express a thyroid-specific set of genes for thyroglobulin (Tg), thyroperoxidase, and the transcription factors TTF-1, TTF-2, and Pax-8. The implication of the small GTPase RhoA in TSH-mediated proliferation of FRTL-5 rat thyroid cells has been previously demonstrated. To further analyze RhoA function in thyroid cell proliferation and differentiation patterns, we combined transient and stable transfection assays to express different mutant RhoA forms in FRTL-5 cells. Constitutively active RhoA (FRTL-5-RhoA QL cells) exhibited a fibroblast-like phenotype with organized actin fibers, whereas cells expressing the RhoA negative dominant phenotype (FRTL-5-RhoA N19 cells) present a rounded morphology and lose normal cytoskeletal architecture. In addition, expression of the constitutively active form of RhoA results in TSH-independent proliferation and anchorage-independent growth and induces tumors when inoculated in nude mice. Interestingly, FRTL-5-RhoA QL cells express less Tg and TTF-1 than wild-type FRTL-5 (FRTL-5- vector) or FRTL-5-RhoA N19, suggesting a loss at the differentiation stage. This effect is mediated, at least in part, by a decrease in TTF-1 activity, since transient or stable expression of RhoA QL results in a reduction in the activity of the wild-type Tg promoter as well as an artificial promoter the activation of which depends exclusively on TTF-1. The similarity between RhoA effects and thyroid transformation by Ras suggests that RhoA may act as a downstream effector of Ras; in fact, the dominant negative RhoA N19 abolished the down- regulatory effect of Ras V12 over the Tg promoter. Taken together, these results show for the first time that active RhoA is able to transform FRTL-5 cells and that this effect is coupled to a loss of thyroid differentiation due to impaired TTF-1 activity.

Author-supplied keywords

  • Animals
  • Carcinogenicity Tests
  • Cell Differentiation
  • Cell Differentiation: drug effects
  • Cell Differentiation: physiology
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Mice
  • Mice, Nude
  • Mutation
  • Nuclear Proteins
  • Nuclear Proteins: genetics
  • Nuclear Proteins: metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-fos: genetics
  • Proto-Oncogene Proteins c-fos: metabolism
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-jun: genetics
  • Proto-Oncogene Proteins c-jun: metabolism
  • Rats
  • Thyroglobulin
  • Thyroglobulin: genetics
  • Thyroglobulin: metabolism
  • Thyroid Gland
  • Thyroid Gland: metabolism
  • Thyroid Gland: pathology
  • Thyrotropin
  • Thyrotropin: metabolism
  • Thyrotropin: pharmacology
  • Transcription Factors
  • Transcription Factors: genetics
  • Transcription Factors: metabolism
  • rhoA GTP-Binding Protein
  • rhoA GTP-Binding Protein: genetics
  • rhoA GTP-Binding Protein: metabolism

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Get full text


  • Diego L Medina

  • Marcos Rivas

  • Patricia Cruz

  • Isabel Barroso

  • Javier Regadera

  • Pilar Santisteban

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free