Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells.
p53-deficient mouse embryonic fibroblasts were used to establish a direct mechanism of tumor suppression by p53 involving the destruction of oncogene-expressing cells by apoptosis. The absence of p53 enhanced cell growth, appeared sufficient for immortalization, and allowed a single oncogene [adenovirus early region 1A (E1A)] to transform cells to a tumorigenic state. p53 suppressed transformation of E1A-expressing cells by apoptosis. Apoptosis was associated with p53 stabilization and was triggered by environmental signals that normally suppress cell growth. Absence of even a single p53 allele significantly enhanced cell growth and survival. Although abrogation of apoptosis allowed transformation by E1A alone, escape from apoptosis susceptibility was not a prerequisite for tumor growth. Consequently, p53 mutation could enhance the survival of malignant cells expressing oncogenes activated early in tumor progression.
Lowe
S W
SW
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139.
Jacks
T
T
Housman
D E
DE
Ruley
H E
HE
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D016159:Tumor Suppressor Protein p53