Mutations and deletions of the CBP gene in human lung cancer.
OBJECTIVE
Microarray-based comparative genomic hybridization analysis led us to detect a homozygous deletion at the cyclic AMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive analysis of genetic CBP alterations in human lung cancer.


METHODS
Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene.


RESULTS
Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examined. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant reduction in transcription activation activity of CBP protein in vivo.


CONCLUSIONS
A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.
Kishimoto
Masahiro
M
Biology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-Chome Chuo-Ku, Tokyo 104-0045, Japan.
Kohno
Takashi
T
Okudela
Koji
K
Otsuka
Ayaka
A
Sasaki
Hiroki
H
Tanabe
Chikako
C
Sakiyama
Tokuki
T
Hirama
Chie
C
Kitabayashi
Issay
I
Minna
John D
JD
Takenoshita
Seiichi
S
Yokota
Jun
J
D000123:Acetyltransferases / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein; D004273:DNA, Neoplasm / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004273:DNA, Neoplasm; D014157:Transcription Factors; D000123:Acetyltransferases