Function of the homeo and paired domain proteins TTF-1 and Pax-8 in thyroid cell proliferation

The thyroid transcription factors TTF-1 and Pax-8 are homeobox- and paired box-containing genes, respectively, that are responsible for thyroid-specific gene expression, thyroid development, and thyroid cell differentiation. However, it is not clear if such factors play a role in thyroid cell proliferation. The antisense oligonucleotide strategy was used in order to clarify this point. Treatment of quiescent FRTL-5 thyroid cells with TTF-1 or Pax-8 antisense oligonucleotides caused a significant reduction in thyroid-stimulating hormone and insulin-like growth factor-I-stimulated cell proliferation, measured by DNA synthesis and cell counting. The same results were obtained with forskolin indicating that the TTF-1 or Pax-8 role in mediating the thyroid-stimulating hormone growth effect occurred via the cAMP pathway. The effect was higher with TTF-1 as the blockage by this factor caused a 65% decrease in cell proliferation compared to the control. Pax-8 blocking lead only to a 30% decrease. The blocking of both thyroid transcription factors together did not result in an additive effect. These data provide direct evidence that both homeo and paired box gene expression is essential for FRTL-5 thyroid cell proliferation, with each one possibly playing a different regulatory role.