A polymorphism but no mutations in the GADD45 gene in breast cancers.
The p53 gene product is part of a pathway regulating growth arrest at the G1 checkpoint of the cell cycle. Mutation of other components of this pathway, including the products of the ataxia telangiectasia (AT), GADD45, mdm2, and p21WAF1/CIP1 genes may have effects comparable to mutations in the p53 gene. The GADD45 gene is induced by ionizing radiation and several DNA-damaging xenobiotics. Induction requires the binding of wild-type p53 to an evoulutionarily highly conserved putative intronic p53 binding site in intron 3 of GADD45. We recently analyzed the entire coding region of the p53 gene in primary breast cancers of Midwestern white women and found 21 mutations among 53 tumors (39.6%). We now have shown by direct sequencing that there are no mutations in the intronic p53 binding site of the GADD45 gene in any of the 53 primary breast cancers and no mutations in the entire coding region of the GADD45 gene in a subset of 26 consecutive tumors (12 with p53 mutation and 14 without p53 mutation). The only sequence variation detected was a common polymorphism in intron 3. The absence of mutations in the GADD45 gene, including the putative p53-binding intronic site, suggests that this gene is not a frequent target of mutations in breast cancer. Although mutations of the p53 gene have been studied in a wide spectrum of human cancers, GADD45 has not been examined in any tumor or cell line to the best of our knowledge. Our results raise the possibility that mutation of the GADD45 gene alone is not functionally equivalent to loss of wild-type p53 activity.
Blaszyk
H
H
Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Hartmann
A
A
Sommer
S S
SS
Kovach
J S
JS
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D000097642:GADD45 Proteins