P53 REEXPRESSION INHIBITS PROLIFERATION AND RESTORES DIFFERENTIATION OF HUMAN THYROID ANAPLASTIC CARCINOMA-CELLS

Alterations of the tumor suppressor gene p53 are uncommon in different iated thyroid neoplasia but are detected at high frequency in anaplast ic thyroid carcinoma suggesting that impaired p53 function may contrib ute to the undifferentiated and highly aggressive phenotype of these t umors, Effects of wild type p53 (wt-p53) re-expression were investigat ed in a human anaplastic thyroid carcinoma cell line (ARO) expressing a mutated p53, ARO cells were stably transfected with the temperature- sensitive p53 Val(135) gene (ts-p53) which exhibits wild type-like act ivity at 32 degrees C, Exogenous wt-p53 function in ARO-tsp53 clones w as assessed by evaluating its transcriptional activity on a CAT report er vector containing p53 binding sites, At 32 degrees C, a significant reduction in the proliferation rate (congruent to 50%) was observed, with accumulation of cells in the G(0)/G(1) phase of the cell cycle, T his effect was accompanied by induction of the expression of the growt h inhibitor p21/Waf1 gene, At 32 degrees C, ARO-tsp53 clones also show ed a marked impairment of their tumorigenic potential, Furthermore, tr ansfected clones re-acquired the ability to respond to thyrotropin (TS H) stimulation showing an increased expression of thyroid-specific gen es (thyroglobulin, thyroperoxidase and TSH receptor), In conclusion, r e-expression of wt-p53 activity in ARO cells, inhibits cell proliferat ion and restores responsiveness to physiological stimuli.