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

Ludwig Institute for Cancer Research [O. B., H-J. S. H., W. K. C.], Department of Medicine [H-J. S. H., W. K. C.], and Center for Molecular Genetics [W. K. C.], University of California San Diego, La Jolla, California 92093-0660

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.

¹ Supported by the California Division of the American Cancer Society, Fellowship 1-62-95 (to O. B.).

² To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660.

Received 5/ 3/95. Accepted 5/19/95.

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