Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4

• Published in: Oncogene Vol. 21; no. 33; pp. 5135 - 5147
• Main Authors: FORSYTH, Nicholas R, MORRISON, Vivienne, BRYCE, Steven D, PARKINSON, E. Kenneth, CRAIG, Nicola J, FITZSIMMONS, Sara A, BARR, Nighean I, IRELAND, Hazel, GORDON, Katrina E, DOWEN, Sally, CUTHBERT, Andrew P, NEWBOLD, Robert F
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 01-08-2002; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Biotechnology; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Survival; Cell Transformation, Neoplastic - genetics; Chromosome 4; Chromosome deletion; Chromosome Mapping; Chromosome Painting; Chromosomes; Chromosomes, Human, Pair 4 - genetics; Cyclin-dependent kinase inhibitors; Diagnosis; DNA-Binding Proteins; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene therapy; Genes; Genetic aspects; Genotype & phenotype; Health aspects; Health. Pharmaceutical industry; Heterozygosity; Humans; Hybrids; In Situ Nick-End Labeling; Industrial applications and implications. Economical aspects; INK4 protein; Loss of heterozygosity; Loss of Heterozygosity - genetics; Mice; Microsatellite Repeats - genetics; Mortality; p53 Protein; Phenotype; Phenotypes; RNA-directed DNA polymerase; Senescence; Squamous cell carcinoma; Telomerase; Telomerase - antagonists & inhibitors; Telomerase - metabolism; Telomerase reverse transcriptase; Telomere - metabolism; Telomere - pathology; Telomeres; Tumor Cells, Cultured; Tumor proteins; United Kingdom > UK; Human; Squamous cell carcinoma; Malignant tumor; Chromosome 4; Gene; Mortality
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205688

Squamous cell carcinoma (SCC) immortality is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) of other chromosomes, including chromosome 4. To test for a functional cancer mortality gene on human chromosome 4 we introduced a complete or fragmented copy of the chromosome into SCC lines by microcell-mediated chromosome transfer (MMCT). Human chromosome 4 caused a delayed crisis, specifically in SCC lines with LOH on chromosome 4, but chromosomes 3, 6, 11 and 15 were without effect. The introduction of the telomerase reverse transcriptase into the target lines extended the average telomere terminal fragment length but did not affect the frequency of mortal hybrids following MMCT of chromosome 4. Furthermore, telomerase activity was still present in hybrids displaying the mortal phenotype. The MMCT of chromosomal fragments into BICR6 mapped the mortality gene to between the centromere and 4q23. Deletion analysis of the introduced chromosome in immortal segregants narrowed the candidate interval to 2.7 Mb spanning D4S423 and D4S1557. The results suggest the existence of a gene on human chromosome 4 whose dysfunction contributes to the continuous proliferation of SCC and that this gene operates independently from telomeres, p53 and INK4A.