LOSS OF WILD-TYPE P53 BESTOWS A GROWTH ADVANTAGE ON PRIMARY CORTICAL ASTROCYTES AND FACILITATES THEIR IN-VITRO TRANSFORMATION

Primary cortical astrocytes were isolated from normal(+/+), heterozygo us (+/-), or homozygous (-/-) p53-knockout mice. The normal astrocytes grew slowly and underwent crisis after limited division, while the ho mozygously defective cells grew rapidly and without contact inhibition . These -/- cells could not initially form colonies in soft agarose bu t acquired this capability after 10 passages in FCS or basic fibroblas t growth factor but not epidermal growth factor. Almost all -/- astroc ytes weakly expressed glial fibrillary acidic protein at passage 10 an d were also A2B5(+) when cultured in basic fibroblast growth factor. M ost heterozygous cells resembled normal ones; however, some survived c risis, grew rapidly, and formed colonies, Outgrowing cells had all los t the wild-type p53 allele. These molecular and cellular events mimic the early stages of human brain tumors, suggest a role for p53 in the earliest stages of disease progression, and provide an experimental sy stem to analyze the effects of other tumor-specific mutations in the d isease process.