Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1) |
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Authors: | Diana M Pitterle Young-Chul Kim Ethel MC Jolicoeur Youjia Cao Kathy C O'Briant Gerold Bepler |
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Institution: | (1) Department of Medicine, P.O. Box 2610, Duke University Medical Center, Durham, North Carolina 27710, USA, US |
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Abstract: | LOH11A is a region of Chromosome (Chr) 11p15.5 where 75% of lung cancers show loss of heterozygosity (LOH). Clinical and
cell biological studies suggest that LOH11A contains a tumor/metastasis suppressor gene. We have mapped this region (650 kb)
using overlapping genomic P1/PAC/BAC clones, and one of the genes that we have identified is RRM1. This gene encodes the large
subunit (M1) of ribonucleotide reductase, the heterodimeric enzyme that catalyzes the rate-limiting step in deoxyribonucleotide
synthesis. By comparing our genomic sequences with the previously published cDNA, we have found that the human gene is composed
of 19 exons. It is oriented telomere to centromere and is Alu rich. In order to verify that RRM1 maps within the boundaries
of LOH11A, we assessed the frequency of LOH at a SacI polymorphism within intron IX of the gene. We observed LOH in 48% (15/31) of informative lung tumor specimens. To determine
whether RRM1 was mutated in tumors, SSCP analysis of the 19 RRM1 exons was performed. No mutations were revealed in 12 pairs
of normal and tumor DNA samples. Immunoblots on protein extracts from normal/tumor pairs indicated that a protein of the expected
size was present in both. Our conclusion is that RRM1 lies within the LOH11A region, but that its exons are not mutated in
tumors. The potential for RRM1 to act as a tumor suppressor is discussed.
Received: 18 September 1998 / Accepted: 10 May 1999 |
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