Lack of somatic mutation in the coding sequence of SIAH1 in tumors hemizygous for this candidate tumor suppressor gene.
The human homolog of the Drosophila seven in absentia gene (SIAH1) may play an important role in apoptosis and tumor suppression. Transcription of SIAH1 is up-regulated in non-tumorigenic clonal populations of cells derived from 2 different tumorigenic parental cell lines. Intracellular SIAH1 mRNA concentration increases in intestinal cells as they migrate from the bottom of the crypt to the lumen, where they undergo apoptosis. Finally, SIAH1 is located on chromosome 16q12-q13, a region that is frequently deleted in a large variety of human tumors. These observations suggest SIAH1 as a candidate tumor suppressor gene that may be inactivated during tumorigenesis. To test this hypothesis, a search for mutation in the coding sequence of this gene was initiated in tumors exhibiting loss of heterozygosity (LOH) at 16q12-q13. No difference was found in 12 hepatocellular carcinomas, 19 breast carcinomas, 9 prostate carcinomas, 7 colon carcinomas and 5 human cell lines derived from colon cancer. One silent sequence variant (C to T transition at amino acid 270) was observed in the FET colon carcinoma cell line. It was subsequently found once in a group of 100 unrelated individuals from the CEPH families. A rapid real-time quantitative RT-PCR fluorescent method shows that SIAH1 remained transcriptionally active in the 6 colon cancer-derived cell lines, and the expression is comparable to the normal colon tissue. Taken together, these observations suggest that although many tumors may have lost one SIAH1 allele, the second allele would not be the site of frequent somatic mutations and may even remain functional.
Medhioub
M
M
Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.
Vaury
C
C
Hamelin
R
R
Thomas
G
G
D000483:Alleles; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins