Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma

Fukuma, Mariko; Okita, Hajime; Hata, Jun Ichi; Umezawa, Akihiro

doi:10.1038/sj.onc.1206055

Cited by 102 publications

(84 citation statements)

References 34 publications

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“…These results suggested that Id-2 promotes neoplastic transformation of oesophageal epithelial cells. Id-2 has been shown to bind and inhibit the function of retinoblastoma protein, a tumour suppressor protein (Iavarone et al, 1994;Lasorella et al, 1996) and therefore has been implicated in tumour progression in several cancer types (Maruyama et al, 1999;Fukuma et al, 2003;Coppe et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma

Chan

et al. 2007

Br J Cancer

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Id protein family consists of four members namely Id-1 to Id-4. Different from other basic helix -loop -helix transcription factors, they lack the DNA binding domain. Id proteins have been shown to be dysregulated in many different cancer types and their prognostic value has also been demonstrated. Recently, Id-1 has been shown to be upregulated in oesophageal squamous cell carcinoma (ESCC). However, the prognostic implications of Id proteins in ESCC have not been reported. We examined the expression of the Id proteins in ESCC cell lines and clinical ESCC specimens and found that Id protein expressions were dysregulated in both the ESCC cell lines and specimens. By correlating the expression levels of Id proteins and the clinicopathological data of our patient cohort, we found that M1 stage tumours had significantly higher nuclear Id-1 expression (P ¼ 0.012) while high nuclear Id-1 expression could predict development of distant metastasis within 1 year of oesophagectomy (P ¼ 0.005). In addition, high levels of Id-2 expression in both cytoplasmic and nuclear regions predicted longer patient survival (P ¼ 0.041). Multivariate analysis showed that high-level expression of Id-2 in both cytoplasmic and nuclear regions and lower level of nuclear Id-1 expression were independent favourable predictors of survival in our ESCC patients. Our results suggest that Id-1 may promote distant metastasis in ESCC, and both Id-1 and Id-2 may be used for prognostication for ESCC patients.

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Section: Discussionmentioning

confidence: 99%

Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma

Chan

et al. 2007

Br J Cancer

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“…At least some of these might represent direct or indirect target genes for the EWS-FLI1 oncoprotein. For example, inhibitor of DNA binding 1 and 2 (ID1; ID2) are inducible by EWS-FLI1 and have been identified independently 33 as marker proteins for EWS. Additional interesting candidates validated by our study include FCGRT, CITED2, fasassociated phosphatase (PTPN13), LNK and FVT1.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 Furthermore, ID2 was recently identified as a target gene of the EWS-FLI1 fusion protein. 33 An interesting group of EWS-specific markers is represented by the DNA-binding proteins CAAT/enhancer binding protein beta (CEBPB) and CBP/p300-interacting transactivator (CITED2). 40 Members of the CITED family specifically bind CREB-binding protein or the transcriptional coactivator p300 and modulate regulation of mRNA gene transcription.…”

Section: Differentiation-related Genes Specific For Ewsmentioning

confidence: 99%

Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing's sarcoma

Baer

Nees

Breit

et al. 2004

Intl Journal of Cancer

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Using Affymetrix oligonucleotide microarrays, we analyzed mRNA gene expression patterns of 12 primary pediatric rhabdomyosarcomas (RMS) and 11 Ewing's sarcomas (EWS), which belong to the small round blue cell tumors (SRBCTs). Diagnostic classification of these cancers is frequently complicated by the highly similar appearance in routine histology, and additional molecular markers could significantly improve tumor classification. A combination of three independent statistical approaches (t-test, SAM, k-nearest neighborhood analysis) resulted in 101 highly significant probe sets that clearly discriminate between EWS and RMS. We identified novel marker transcripts that have not been previously associated with either RMS or EWS yet, including CITED2, glypican 3 (GPC3), and cyclin D1 (CCND1). Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR. Furthermore, to identify biologically meaningful trends, functional annotations were assigned to 946 genes differentially expressed between EWS and RMS (t-test). Genes involved in protein biosynthesis (n ‫؍‬ 28) and complex assembly (n ‫؍‬ 9), lipid metabolism (n ‫؍‬ 23), energy generation (n ‫؍‬ 22), and mRNA processing (n ‫؍‬ 11) were expressed significantly higher in EWS. Thus, functional annotation of tumor-specific genes reveals detailed insights into tumor biology and differentiation-specific expression patterns and gives important clues related to the possible cellular origin of these pediatric tumors. Small round blue cell tumors (SRBCTs) are frequently difficult to distinguish by standard histology or, sometimes, even by immunohistochemistry. Rhabdomyosarcoma (RMS) and Ewing's sarcomas (EWS) are common pediatric solid tumors that belong to this group that also includes neuroblastoma and Burkitt's lymphoma. However, the correct diagnosis of SRBCT tumors is essential since treatment regimens, response to therapy and prognosis may differ markedly. Therefore, molecular techniques are increasingly implemented for the diagnostic distinction of SRBCT tumors, including EWS and RMS. Progress in recent years includes the identification of characteristic tumor-specific chromosomal translocations, resulting in the expression of aberrant, oncogenic fusion proteins.RMS is the most common pediatric soft tissue sarcoma and can be histologically subdivided into the more prevalent embryonal (eRMS) and the more aggressive alveolar rhabdomyosarcoma (aRMS). ARMS have an unfavorable prognosis due to a tendency to early relapses and frequent failure of chemotherapy. This is reflected by 5-year survival rates ranging between 20 -50%. Most aRMS express PAX3-FKHR or PAX7-FKHR fusion proteins resulting from [t(2;13)(q35;q14)] or [t(1;13)(p36;q14)] translocations, respectively. 1-3 Although a frequently affected chromosomal locus in eRMS has been defined (11p15.5), specific gene(s) or a fusion transcript have not been identified. 4 Ewing's sarcomas (EWS) and the related, more differentiated peripheral neuroectodermal tumors (PNET) are...

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“…Among them, Id2 has been extensively studied in several cell types and in animal models and found to be not only an inhibitor of differentiation but also a positive regulator of cell proliferation and oncogenesis (5,6,8). Aberrant elevation of Id2, typically activated by oncoproteins such as Myc and Ews-Fli1, was frequently observed in tumors from the central and peripheral nervous system (9)(10)(11)(12). The aberrant accumulation of Id2 contributes to uncontrolled proliferation and neoangiogenesis, two hallmarks of neural cancers (13).…”

Section: Introductionmentioning

confidence: 99%

FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells

Han

Zhao

et al. 2009

Chin. J. Cancer Res.

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Inhibitor of differentiation 2 (Id2) is a natural inhibitor of the basic helix-loop-helix transcription factors. Although Id2 is well known to prevent differentiation and promote cell-cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Here, we identified that Four-and-a-half LIM-only protein 2 (FHL2) is a novel functional repressor of Id2. Moreover, we demonstrated that FHL2 can directly interact with all members of the Id family (Id1-4) via an N-terminal loop-helix structure conserved in Id proteins. FHL2 antagonizes the inhibitory effect of Id proteins on basic helix-loop-helix protein E47-mediated transcription, which was abrogated by the deletion mutation of Ids that disrupted their interaction with FHL2. We also showed a competitive nature between FHL2 and E47 for binding Id2, whereby FHL2 prevents the formation of the Id2-E47 heterodimer, thus releasing E47 to DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acidinduced differentiation of neuroblastoma cells, during which the expression of Id2 was opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Altogether, these results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.

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Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma

Cited by 102 publications

References 34 publications

Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma

Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma

Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing's sarcoma

FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells

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