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 (+/+), heterozygous (+/-), or homozygous (-/-) p53-knockout mice. The normal astrocytes grew slowly and underwent crisis after limited division, while the homozygously defective cells grew rapidly and without contact inhibition. These -/- 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 -/- astrocytes weakly expressed glial fibrillary acidic protein at passage 10 and were also A2B5+ when cultured in basic fibroblast growth factor. Most heterozygous 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 mimic the early stages of human brain tumors, suggest a role for p53 in the earliest stages of disease progression, and provide an experimental system to analyze the effects of other tumor-specific mutations in the disease process.
Bögler
O
O
Ludwig Institute for Cancer Research, California San Diego, La Jolla 92093-0660, USA.
Huang
H J
HJ
Cavenee
W K
WK
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology*; D002471:Cell Transformation, Neoplastic; D002540:Cerebral Cortex / Q000166:cytology*; D005260:Female; D016158:Genes, p53; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout