CBP truncating mutations in ovarian cancer

Abstract

T he CBP gene (OMIM #600140) encodes the 2441 amino acid cyclic AMP response element binding protein (CREB) binding protein (Mr 265 000) that functions as an essential co-activator for a number of transcription factors. 1 In particular, CBP, like its homologue EP300, enhances gene transcription by linking sequence specific transcription factors to transcription factor IIB and the RNA polymerase II holoenzyme.2 CBP can also promote gene transcription by acetylation of histones through its histone acetyltransferase activity (HAT) 3 and by acetylation of specific transcription factors such as p53. [4][5][6] Several lines of evidence suggest the involvement of CBP in tumour formation. CBP interacts with the human T cell leukaemia virus (HTLV) Tax protein and v-myb to induce viral and cellular genes that promote cell transformation, while adenovirus E1A, simian virus SV40 Tag, and human papillomavirus (HPV) E6 bind to CBP and inhibit its co-activator function. CBP is also known to modulate the actions of the hMDM2 and AML1 cellular proto-oncogenes and the BRCA1 and p53 tumour suppressors.7 More direct evidence comes from genetic studies of translocation events involving CBP in leukaemia. In particular, the t(8;16)(p11;p13) translocation in AML involves a fusion of the CBP and MOZ genes, 8 a novel t(10;16)(q22;p13) translocation in a childhood acute myelogenous leukaemia (AML-M5a) generates a MORF-CBP chimera, 9 and the t(11;16)(q23;p13.3) translocation in topoisomerase II treated acute leukaemia or myelodysplasia results in a MLL-CBP fusion. 10 In addition, haploinsufficiency of CBP in humans due to chromosomal rearrangements, microdeletions, and point mutations results in RubensteinTaybi Syndrome (RTS), and is associated with an increased risk for a variety of tumours. 11As a result of these observations, a number of studies have evaluated whether CBP is a direct mutational target in cancer and has tumour suppressor activity. One recent mutation screening study of CBP in breast, ovarian, and colorectal tumours and cell lines identified two CBP truncating mutations in ovarian cancer cell lines, but failed to detect mutations in the tumours. 12 Haematological malignances displaying loss of heterozygosity (LOH) at the CBP locus have been detected in aged CBP heterozygous mice, 13 and in chimeric mice derived from CBP -/-embryonic stem cells. 14 In addition, recent studies using an MMTV driven conditional knockout mouse model demonstrated that truncation of the CBP protein in the thymus results in development of T cell lymphomas, 15 suggesting that targeted mutations in CBP can predispose to cancer. To determine whether CBP is a mutational target in human epithelial cancers, and specifically to evaluate the presence of CBP mutations in breast and ovarian tumours, we conducted a mutational analysis of the CBP gene. MATERIALS AND METHODS Sample selectionA total of 75 unselected surgically resected fresh frozen ovarian tumour specimens and 61 unselected fresh frozen breast tumour specimens were obtained from the ovarian an...

Metabolic Consequences of p300 Gene Deletion in Human Colon Cancer Cells

“…The decrease in glutamate and glutamine concentrations suggests that mitochondrial oxidation of these substrates may be increased. However, the transcript levels of glutamate dehydrogenase (a mitochondrial enzyme responsible for glutamate and glutamine utilization) were reduced in p300 À cells, 4 which is inconsistent with this notion. Instead, the changes in glutamate and glutamine levels may reflect some wider perturbation of the metabolic network that has no direct connection with p300 function, as glutamate is one of the most highly connected compounds in cellular metabolism.…”

“…In fact, few studies even attempt to make the distinction despite mounting evidence that the homologues do play separate roles. Supporting this fact, it is evident that p300 and CREB-binding protein are mutated in different epithelial tumor types, suggesting different roles in carcinogenesis (2)(3)(4)(5). Thus, it would be useful to have a comprehensive method for assessing the overall global effect of p300 gene deletion on cellular physiology.…”

“…4 However, it is not currently possible to use these data to make predictions of the metabolic consequences of p300 loss. Hence, a comprehensive metabolic assessment-metabolomics-is necessary to fully delineate the cellular phenotype resulting from p300 gene deletion.…”

cAMP response element–binding protein is expressed at high levels in human ovarian adenocarcinoma and regulates ovarian tumor cell proliferation

“…With respect to genes that interact with CREB, it has been shown that the CBP gene is mutated in ovarian tumors. Ward et al (41) found that CBP was mutated (frameshift mutation) in 2 of 75 epithelial ovarian tumors that were examined. It was hypothesized that these mutations resulted in inactivation of CBP function.…”

Epigenetic therapy of cancer with histone deacetylase inhibitors

“…[7][8][9] Mutations of HAT proteins have been identified in colorectal, breast, prostate, gastric and ovarian cancer. [10][11][12][13] Therefore, the inhibition of HDACs is a rational target for the development of novel anticancer therapy.…”