Oncogene database

3398

ID2

inhibitor of DNA binding 2, dominant negative helix-loop-helix protein;ID2;inhibitor of DNA binding 2, dominant negative helix-loop-helix protein

DNA-binding protein inhibitor ID-2|DNA-binding protein inhibitor ID2|cell growth-inhibiting gene 8|class B basic helix-loop-helix protein 26|helix-loop-helix protein ID2|inhibitor of differentiation 2

2p25

protein-coding

Perturbation of the function of the retinoblastoma (Rb) protein is found in most human tumors. Id2 is a natural target of the Rb protein that is recruited by Myc oncoproteins to bypass the tumor suppressor function of Rb. Here we report that an "N-Myc-Id2 pathway" persists during late development of the nervous system and parallels the rising levels of active Rb in neuronal precursors withdrawing from the cell cycle. An immunohistochemical analysis of primary neuroblastoma from 47 patients shows that expression of Id2 is strongly predictive of poor outcome, irrespective of other clinical and biological variables. Overexpression of Id2 mediates cellular transformation and is required to maintain the malignant behavior of neuroblastoma cells. Correspondingly, embryonic fibroblasts from Id2-null mice display impaired ability to proliferate. We suggest that Id2 overexpression may be a better prognostic indicator than N-myc gene amplification in neuroblastoma. Thus, disrupting Id2 function may lead to new and useful therapeutic strategies for cancer patients.

The chromosomal translocation specifically linked to the Ewing sarcoma family results in the generation of fusion proteins comprising the amino terminal portion of EWS and the DNA-binding domain of ets transcription factors. The EWS/ets chimeric proteins act as aberrant transcription factors leading to tumorigenic processes. We searched for genes specifically activated in Ewing sarcoma cells but not in other tumor cell lines using the gene array technique, and found significantly enhanced expression of the Id2 gene. High levels of Id2 transcripts were detected in Ewing sarcoma cell lines and tumor tissues. The EWS/ets chimeric proteins activated the Id2 gene via the 5 -upstream promoter sequence. Chromatin-immunoprecipitation revealed a direct interaction of EWS/Fli-1 with the promoter regions of the Id2, TGF-beta type II receptor, cyclin D1, and c-myc genes. Since EWS/Fli-1 transactivates c-myc, a cooperative action of the chimeric protein and c-myc leads to overexpression of Id2. In the present study, we suggest that Id2 is a target of the chimeric proteins and that the c-myc/Id2 pathway plays a pivotal role in the tumorigenic processes provoked by EWS/ets proteins.

AIMS AND BACKGROUND: Id helix-loop-helix proteins function as regulators of cell growth and differentiation. However, they can induce malignant transformation when overexpressed. The EWS/ETS chimeric proteins in Ewing sarcoma act as aberrant transcription factors leading to tumorigenic processes. An enhanced expression of the Id2 gene in Ewing sarcoma cells was previously shown by gene array techniques. We investigated the expression of Id2 at the protein and gene level in Ewing sarcoma. METHODS: We evaluated the expression of Id2 protein using immunohistochemistry in formalin-fixed, paraffin-embedded specimens from a total of 71 cases of Ewing sarcoma. Additionally, a Ewing sarcoma cell line was examined by real-time quantitative PCR. RESULTS: Id2 expression was observed in 65 cases (91.5%) of the 71 total cases examined and a high level of Id2 expression was observed in 45 of these cases (63.8%). In tumor cells, Id2 proteins displayed cytoplasmic as well as nuclear localization. The amplification of the Id2 gene was not noted in a Ewing sarcoma cell line using real-time quantitative PCR. The crossing points of Id2 in the Ewing sarcoma cell line, control fibroblast, and osteosarcoma cell line were 18.54 +/- 0.16, 18.25, and 18.34, respectively. CONCLUSIONS: Our data support a role for increased Id2 protein expression in Ewing sarcoma. However, this overexpression of the Id2 protein could not be confirmed by a corresponding change at the gene level in a Ewing sarcoma cell line.