Abrogation of Oncogene-Associated Apoptosis Allows Transformation of p53- Deficient Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 6; pp. 2026 - 2030
• Main Authors: Lowe, Scott W., Jacks, Tyler, Housman, David E., Ruley, H. Earl
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15-03-1994; National Acad Sciences; National Academy of Sciences
• Subjects: adenovirus; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Adenoviruses; Animals; Apoptosis; Apoptosis - genetics; Biological and medical sciences; Cell cycle; Cell Division; Cell growth; Cell Line; Cell lines; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cells; Cellular biology; Fibroblasts; Fibroblasts - cytology; Fundamental and applied biological sciences. Psychology; Genes; Male; Mice; Mice, Nude; Molecular and cellular biology; Mutation; Oncogenes; Rodents; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Viability; Cell proliferation; Vertebrata; Mammalia; Mouse; Cell death; C-Onc gene; Rodentia; Mutation; Cell transformation; Fibroblast; Tumor suppressor gene; Apoptosis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.6.2026

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.