23261

CAMTA1

-;calmodulin binding transcription activator 1;CAMTA1;calmodulin binding transcription activator 1

calmodulin-binding transcription activator 1

1p36.31-p36.23

protein-coding

Count: 2; Pubmed_search,Generif

A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G(1)/G(0) phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma.CI - (c)2011 AACR.

PURPOSE: Allelic loss at 1p is seen in 70% to 85% of oligodendrogliomas (typically in association with 19q allelic loss) and 20-30% of astrocytomas. Because most 1p deletions in gliomas involve almost the entire chromosome arm, narrowing the region of the putative tumor suppressor gene has been difficult. To better define the histologic correlates of different patterns of 1p and 19q loss, we evaluated 1p/19q status in a large group of gliomas. This also allowed us to define a very small minimal deleted region (MDR) on 1p36. EXPERIMENTAL DESIGN: Among 205 consecutive cases of glioma studied for 1p loss of heterozygosity (LOH), 112 tumors were evaluated for both 1p and 19q LOH using at least three polymorphic markers on 1p and 19q each. The latter group included both low-grade tumors (oligodendroglioma, diffuse astrocytoma, and "oligoastrocytoma") and high-grade tumors (anaplastic oligodendrogliomas, anaplastic astrocytomas, anaplastic oligoastrocytomas). Tumors with small segmental 1p losses (defined as LOH at some loci with retention of heterozygosity at other loci) were studied using a more extensive panel of markers to define the 1p MDR. The candidate gene was screened for mutations and its expression was studied by qualitative and quantitative reverse transcriptase-PCR and Northern blotting. RESULTS: Allelic losses on 1p and 19q, either separately or combined, were more common in classic oligodendrogliomas than in either astrocytomas or oligoastrocytomas (P < 0.0001). Classic oligodendrogliomas showed 1p loss in 35 of 42 (83%) cases, 19q loss in 28 of 39 (72%), and these were combined in 27 of 39 (69%) cases. There was no significant difference in 1p/19q LOH status between low-grade and anaplastic oligodendrogliomas. In contrast, no astrocytomas and only 6 of 30 (20%) oligoastrocytic tumors had combined 1p/19q loss. Although rare, 1p deletions were more often segmental in astrocytomas (5 of 6, 83%) than in oligodendrogliomas (3 of 35, 9%; P = 0.006). Eleven tumors (6 oligodendrogliomas or having oligodendroglial components, 5 purely astrocytic) with small segmental 1p losses underwent further detailed LOH mapping. All informative tumors in the oligodendroglial group and 2 of 3 informative astrocytomas showed LOH at 1p36.23, with a 150-kb MDR located between D1S2694 and D1S2666, entirely within the CAMTA1 transcription factor gene. mutation analysis of the exons encoding conserved regions of CAMTA1 showed no somatic mutations in 10 gliomas, including 6 cases with and 4 cases without 1p LOH. CAMTA1 is normally expressed predominantly in non-neoplastic adult brain tissue. Relative to the latter, the expression level of CAMTA1 was low in oligodendroglial tumors and was further halved in cases with 1p deletion compared with those without 1p deletion (Mann-Whitney, P = 0.03). CONCLUSIONS: Our data confirm the strong association of combined 1p/19q loss with classic oligodendroglioma histology and identify a very small segment of 1p36 located within CAMTA1 that was deleted in all oligodendroglial tumors with 1p LOH. This MDR also overlaps the neuroblastoma 1p36 MDR. CAMTA1 shows no evidence of inactivation by somatic mutations but its expression is reduced by half in cases with 1p LOH, suggesting that the functional effects of CAMTA1 haploinsufficiency warrant further investigation.

tumor suppressor genes of neuroblastoma are located at human chromosome 1p36, 4p16, 11q23.3, and 14q32. We have previously cloned and characterized MFRP and RNF26 genes at 11q23.3. Here, we searched for genes within the 1p36.31-p36.23 commonly deleted region between microsatellite markers D1S2731 and D1S2666 by using bioinformatics. D1S2731 was located within FLJ10737 gene, consisting of 16 exons. D1S2666 was located within CAMTA1 gene, consisting of 23 exons. FLJ10737 and CAMTA1 genes were located in the head-to-head manner with an interval of about 83 kb. Exons 1-10 of FLJ10737 gene as well as exons 1-5 of CAMTA1 gene were located within the 1p36.31-p36.23 commonly deleted region. FLJ10737 (559 aa) was found to consist of the DnaJ domain, bipartite nuclear localization signal (NLS), FADH domain, and FEMCA domain. Mouse E030019A03, zebrafish MGC55845, Drosophila CG8531 and Arabidopsis At2g35720 were homologs of human FLJ10737. FADH domain was conserved among vertebrate FLJ10737 orthologs as well as human AD-015, mouse Histocompatibility 47, and rat Ratsg2. KIAA0833 was the representative human CAMTA1 cDNA. Nucleotide sequence of mouse Camta1 cDNA was determined in silico by assembling nucleotide sequences of BY733411, BU610694 ESTs and AK122383 cDNA. Human CAMTA1 (1673 aa) and mouse Camta1 (1682 aa) showed 94.1% total-amino-acid identity. CAMTA1 was a Calmodulin-binding transcription activator (CAMTA) family protein, consisting of CG-1 domain, TIG domain, ankyrin repeats, and IQ motifs. FLJ10737 and CAMTA1 genes on 1p36.31-p36.23 are candidate tumor suppressor genes of neuroblastoma.