Mutations and Deletions of the <i>CBP</i> Gene in Human Lung Cancer

Clinical Cancer Research - Tập 11 Số 2 - Trang 512-519 - 2005
Masahiro Kishimoto1,2, Takashi Kohno1,3, Koji Okudela1, Ayaka Otsuka1, Hiroki Sasaki3,4, Chikako Tanabe4, Tokuki Sakiyama3,4, Chie Hirama3, Issay Kitabayashi5, John D. Minna6, Seiichi Takenoshita2, Jun Yokota1,3
11Biology Division,
25Second Department of Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan; and
32Center for Medical Genomics,
43Genetics Division, and
54Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan;
66Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas

Tóm tắt

Abstract Purpose: 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. Experimental Design: 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.

Từ khóa


Tài liệu tham khảo

Kohno T, Yokota J. How many tumor suppressor genes are involved in human lung carcinogenesis? Carcinogenesis 1999;20:1403–10.

Sekido Y, Fong KM, Minna JD. Molecular genetics of lung cancer. Annu Rev Med 2003;54:73–87.

Sanchez-Cespedes M. Dissecting the genetic alterations involved in lung carcinogenesis. Lung Cancer 2003;40:111–21.

Giordano A, Avantaggiati ML. p300 and CBP: partners for life and death. J Cell Physiol 1999;181:218–30.

Chan HM, La Thangue NB. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci 2001;114:2363–73.

Panagopoulos I, Fioretos T, Isaksson M, et al. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16) (q22;p13). Hum Mol Genet 2001;10:395–404.

Janknecht R. The versatile functions of the transcriptional coactivators p300 and CBP and their roles in disease. Histol Histopathol 2002;17:657–68.

Miller RW, Rubinstein JH. Tumors in Rubinstein-Taybi syndrome. Am J Med Genet 1995;56:112–5.

Kung AL, Rebel VI, Bronson RT, et al. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev 2000;14:272–7.

Ionov Y, Matsui S, Cowell JK. A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability. Proc Natl Acad Sci U S A 2004;101:1273–8.

So CK, Nie Y, Song Y, et al. Loss of heterozygosity and internal tandem duplication mutations of the CBP gene are frequent events in human esophageal squamous cell carcinoma. Clin Cancer Res 2004;10:19–27.

Ozdag H, Batley SJ, Forsti A, et al. Mutation analysis of CBP and PCAF reveals rare inactivating mutations in cancer cell lines but not in primary tumours. Br J Cancer 2002;87:1162–5.

Tillinghast GW, Partee J, Albert P, et al. Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines. Genes Chromosomes Cancer 2003;37:121–31.

Burbee DG, Forgacs E, Zochbauer-Muller S, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93:691–9.

Nishioka M, Kohno T, Takahashi M, et al. Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line. Oncogene 2000;19:6251–60.

Ishizuka T, Tanabe C, Sakamoto H, et al. Gene amplification profiling of esophageal squamous cell carcinomas by DNA array CGH. Biochem Biophys Res Commun 2002;296:152–5.

Coupry I, Roudaut C, Stef M, et al. Molecular analysis of the CBP gene in 60 patients with Rubinstein-Tybi syndrome. J Med Genet 2002;39:415–21.

Shiseki M, Kohno T, Nishikawa R, et al. Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma. Cancer Res 1994;54:5643–8.

Kitabayashi I, Aikawa Y, Nguyen LA, et al. Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J 2001;20:7184–96.

Hamada K, Kohno T, Takahashi M, et al. Two regions of homozygous deletion clusters at chromosome band 9p21 in human lung cancer. Genes Chromosomes Cancer 2000;27:308–18.

Bartsch O, Locher K, Meinecke P, et al. Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet 2002;39:496–501.

Kalkhoven E, Roelfsema JH, Teunissen H, et al. Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome. Hum Mol Genet 2003;12:441–50.

Murata T, Kurokawa R, Krones A, et al. Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome. Hum Mol Genet 2001;10:1071–6.

Petrij F, Dauwerse HG, Blough RI, et al. Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J Med Genet 2000;37:168–76.

Hennekam RC, Stevens CA, Van de Kamp JJ. Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet 1990;6:56–64.

Yuan LW, Giordano A. Acetyltransferase machinery conserved in p300/CBP-family proteins. Oncogene 2002;21:2253–60.

Martinez-Balbas MA, Bannister AJ, Martin K, et al. The acetyltransferase activity of CBP stimulates transcription. EMBO J 1998;17:2886–93.

Mujtaba S, He Y, Zeng L, et al. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol Cell 2004;13:251–63.

Fujita T, Kiyama M, Tomizawa Y, et al. Comprehensive analysis of p53 gene mutation characteristics in lung carcinoma with special reference to histological subtypes. Int J Oncol 1999;15:927–34.

Muraoka M, Konishi M, Kikuchi-Yanoshita R, et al. p300 gene alterations in colorectal and gastric carcinomas. Oncogene 1996;12:1565–9.

Gayther SA, Batley SJ, Linger L, et al. Mutations truncating the EP300 acetylase in human cancers. Nat Genet 2000;24:300–3.

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Clinical Cancer Research

Tập 11 Số 2

512-519

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