Loss of Wild-Type p53 Bestows a Growth Advantage on Primary Cortical Astrocytes and Facilitates Their in Vitro Transformation1

Primary cortical astrocytes were belated from normal (+1+), heterozy gous (+1—), or homozygous(—/—)p53-knockout mice.The normal astro cytes grew slowly and underwent crisis after limited division, while the homozygously defective cells grew rapidly and without contact inhibition. These —I— cells could not initially form colonies in soft agarose but acquired this capability after 10 passages in FCS or basic fibroblast growth factor but not epidermal growth factor. Almost all —I— astrocytes wealdy expressed glial fibrillary acidic protein at passage 10 and were also A2B5@ when cultured in basic fibroblast growth factor. Most heterozy gous cells resembled normal ones; however, some survived crisis, grew rapidly, and formed colonies. Outgrowing cells had all lost the wild-type p53 allele. These molecular and cellular events manic the early stages of human brain tumors, suggest a role forp53 in the earliest stages of disease progression, and provide an experimental system to analyze the effects of other tumor-specificmutations in the diseaseprocess.