Oncogenes and tumor-suppressor genes.
The functional role of oncogenes in human lung carcinogenesis has been investigated by transfer of activated oncogenes into normal cells or an immortalized bronchial epithelial cell line, BEAS-2B. Transfection of v-Ha-ras, Ki-ras, or the combination of myc and raf into BEAS-2B cells produced tumorigenic cell lines, while transfection of raf or myc alone produced nontumorigenic cell lines. In addition to studying the pathogenic role of oncogenes, we are attempting to define negative growth-regulating genes that have tumor-suppressive effects for human lung carcinomas. Our strategy to identify tumor-suppressor genes involves loss of heterozygosity studies, monochromosome-cell fusion, and cell-cell fusion studies. Loss of heterozygosity studies have revealed consistent allelic DNA sequence deletions on chromosome 17p in squamous cell carcinomas, while large cell carcinomas and adenocarcinomas retained this locus. Mutations in p53, a tumor-suppressor gene located on chromosome 17p, have been observed. Cell-cell hybrid clones produced from fusion of nontumorigenic BEAS-2B cells with tumorigenic HuT292DM cells generally are nontumorigenic. The mechanistic role of the known tumor-suppressor genes Rb-1 and p53 in the development of human lung carcinomas is being investigated in this epithelial cell model of human bronchogenic carcinogenesis.
Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892.
T A
TA
Lehman
R
R
Reddel
A M
AM
Peiifer
E
E
Spillare
M E
ME
Kaighn
A
A
Weston
B I
BI
Gerwin
C C
CC
Harris
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D002459:Cell Fusion; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure; D002886:Chromosomes, Human, Pair 17 / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000235:genetics; D004847:Epithelial Cells; D005134:Eye Neoplasms / Q000235:genetics; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D005816:Genetic Complementation Test; D006360:Heat-Shock Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D006822:Hybrid Cells; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D012150:Polymorphism, Restriction Fragment Length; D012175:Retinoblastoma / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D000952:Antigens, Polyomavirus Transforming; D004273:DNA, Neoplasm; D006360:Heat-Shock Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53