p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells

Alterations of the tumor suppressor gene p53 are uncommon in di€erentiated thyroid neoplasia but are detected at high frequency in anaplastic thyroid carcinoma suggesting that impaired p53 function may contribute to the undi€erentiated and highly aggressive phenotype of these tumors. E€ects of wild type p53 (wt- p53) re-expression were investigated in a human anaplastic thyroid carcinoma cell line (ARO) expressing a mutated p53. ARO cells were stably transfected with the temperature-sensitive p53 Val135 gene (ts-p53) which exhibits wild type-like activity at 328C. Exogenous wt- p53 function in ARO-tsp53 clones was assessed by evaluating its transcriptional activity on a CAT reporter vector containing p53 binding sites. At 328C, a signi®cant reduction in the proliferation rate (%50%) was observed, with accumulation of cells in the G0/G1 phase of the cell cycle. This e€ect was accompanied by induction of the expression of the growth inhibitor p21/ Waf1 gene. At 328C, ARO-tsp53 clones also showed a marked impairment of their tumorigenic potential. Furthermore, transfected clones re-acquired the ability to respond to thyrotropin (TSH) stimulation showing an increased expression of thyroid-speci®c genes (thyroglo- bulin, thyroperoxidase and TSH receptor). In conclu- sion, re-expression of wt-p53 activity in ARO cells, inhibits cell proliferation and restores responsiveness to physiological stimuli.