DIFFERENTIATION IS INHIBITED AND A SENESCENCE PATHWAY IS ACTIVATED WHEN SIMIAN-VIRUS-40 TSA 58-TRANSFORMED HUMAN RETINOBLASTS ARE GROWN AT THE RESTRICTIVE TEMPERATURE

Neonatal human retina cells transformed by the SV40 tumor antigens wer e shown to leave the cell cycle and differentiate following treatment with agents that raise intracellular levels of cyclic AMP. This was tr ue for both precrisis and immortal cell lines. However, with time, som e of the differentiated retinoblasts withdrew neurites and returned to the cell cycle. Attempts to inhibit this process by developing cell l ines transformed using SV tsA 58 with a temperature-sensitive phenotyp e for growth did not enhance but inhibited retinoblast-differentiating capacity. Growth restriction at the nonpermissive temperature was fou nd to activate a senescence pathway. We propose that at the nonpermiss ive temperature, stable SV40 T-ag-p53 complexes fragment releasing p53 , which transactivates p21(waf1/cip1/sdi1) with the subsequent accumul ation of p21 culminating in growth inhibition and senescence.