Genomic cloning of methylthioadenosine phosphorylase: A purine metabolic enzyme deficient in multiple different cancers

Tsutomu Nobori, Kenji Takabayashi, Phuoc Tran, Lisa Orvis, Ayse Batova, Alice L. Yu, Dennis A. Carson

Research output: Contribution to journalArticlepeer-review

Abstract

5'-Deoxy-5'-methylthioadenosine phosphorylase (methylthioadeno-sine: ortho-phosphate methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism and in the regulation of transmethylation reactions. MTAP is abundant in normal cells but is deficient in many cancers. Recently, the genes for the cyclin-dependent kinase inhibitors p16 and p15 have been localized to the short arm of human chromosome 9 at band p21, where MTAP and interferon α genes (IFNA) also map. Homozygous deletions of p16 and p15 are frequent malignant cell lines. However, the order of the MTAP, p16, p15, and IFNA genes on chromosome 9p is uncertain, and the molecular basis for MTAP deficiency in cancer is unknown. We have cloned the MTAP gene, and have constructed a topologic map of the 9p21 region using yeast artificial chromosome clones, pulse-field gel electrophoresis, and sequence-tagged-site PCR. The MTAP gene consists of eight exons and seven introns. Of 23 malignant cell lines deficient in MTAP protein, all but one had complete or partial deletions. Partial or total deletions of the MTAP gene were found in primary T-cell acute lymphoblastic leukemias (T-ALL). A deletion breakpoint of partial deletions found in cell lines and primary T-ALL was in intron 4. Starting from the centromeric end, the gene order on chromosome 9p21 is p15, p16, MTAP, IFNA, and interferon β gene (IFNB). These results indicate that MTAP deficiency in cancer is primarily due to codeletion of the MTAP and p16 genes.

Original languageEnglish (US)
Pages (from-to)6203-6208
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number12
DOIs
StatePublished - Jun 11 1996
Externally publishedYes

Keywords

  • T-cell acute lymphoblastic leukemia
  • chromosome 9p
  • tumor suppressor gene

ASJC Scopus subject areas

  • General

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