58:(EMC) and encodes a transcription factor of the helix-loop-helix family that lacks a DNA binding domain. EMC regulates cell proliferation, formation of organs like the midgut, and wing development. ID proteins could be potential targets for systemic cancer therapies without inhibiting the functioning of most normal cells because they are highly expressed in embryonic stem cells, but not in differentiated adult cells. Evidence suggests that ID proteins are overexpressed in many types of cancer. For example, ID1 is overexpressed in pancreatic, breast, and prostate cancers. ID2 is upregulated in neuroblastoma, Ewing’s sarcoma, and squamous cell carcinoma of the head and neck.
78:. By inhibiting the formation of E-protein dimers that promote differentiation, ID proteins can regulate the timing of differentiation of stem cells during development. An increase in ID expression is seen in embryonic and adult stem cells. ID proteins also promote cell cycle progression, delaying senescence, and help facilitate cell migration. In contrast, inappropriate regulation of ID proteins in differentiated cells can contribute to
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lymph nodes and showed defects in mammary proliferation. Generally, normal development was seen in mice with an ID3 knockout, but they did have a defect in B-cell proliferation. Neural defects and premature differentiation were seen in mice lacking ID4. Knockout of both ID1 and ID3 resulted in embryonic lethality due to brain hemorrhages and abnormalities in cardiac development.
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example, an increase in ID1 expression in brain cancer is correlated with a better prognosis, while a decrease in ID4 expression in colon and rectal cancers is linked to a poorer prognosis. ID proteins can bind E-proteins, preventing them from binding bHLH proteins and halting transcription, a case often seen in cancerous phenotypes.
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proteins can regulate transcription by binding E proteins, so no dimers can be formed and transcription is inactive. E proteins are members of the class I bHLH family and form dimers with bHLH proteins from class II to regulate transcription. Four ID proteins exist in humans: ID1, ID2, ID3, and ID4. The ID homologue gene in
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Perk, Iavarone, and
Benezra, (2005), reviewed fifteen studies and compiled a list of the phenotypic effects of each ID gene when knocked out in mice. When ID1 was knocked out, a defect in T-cell migration was seen. A knockout of ID2 showed that 25% of mice died perinatally, and those born lacked
47:
with bHLH proteins. The first helix-loop-helix proteins identified were named E-proteins because they bind to
Ephrussi-box (E-box) sequences. In normal development, E proteins form dimers with other bHLH transcription factors, allowing transcription to occur. However, in cancerous phenotypes, ID
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halts neuron axon growth and allows elongation of neurons. Knockout mouse data show that ID genes are essential for heart development. There is some controversy surrounding the ID proteins and their role in cancer, but overexpression is seen in most tumor types. There are a few exceptions, for
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which are critical to tumour growth and angiogenesis. This publication has demonstrated that targeting ID1 resulted in decreased tumour growth. Therefore, ID1 could be used to design a novel cancer therapy.
82:. Generally, IDs function as oncogenes. When ID proteins are overexpressed, cell proliferation is enhanced and cells become insensitive to growth factor depletion. Expression of ID proteins in
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Pagliuca A, Bartoli PC, Saccone S, Della Valle G, Lania L (May 1995). "Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22".
725:"Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth"
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Mellick AS, Plummer PN, Nolan DJ, Gao D, Bambino K, Hahn M, Catena R, Turner V, McDonnell K, Benezra R, Brink R, Swarbrick A, Mittal V (September 2010).
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Lasorella A, Benezra R, Iavarone A (February 2014). "The ID proteins: master regulators of cancer stem cells and tumour aggressiveness".
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Kondo M, Cubillo E, Tobiume K, Shirakihara T, Fukuda N, Suzuki H, Shimizu K, Takehara K, Cano A, Saitoh M, Miyazono K (October 2004).
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binding of bHLH proteins. ID proteins also contain the HLH-dimerization domain but lack the basic DNA-binding
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Fong S, Debs RJ, Desprez PY (August 2004). "Id genes and proteins as promising targets in cancer therapy".
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67:
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Iavarone A, Lasorella A (December 2006). "ID proteins as targets in cancer and tools in neurobiology".
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277:"A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation"
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Perk J, Iavarone A, Benezra R (August 2005). "Id family of helix-loop-helix proteins in cancer".
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Cunningham TJ, Yu MS, McKeithan WL, Spiering S, Carrette F, Huang CT, et al. (July 2017).
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A recent publication in Cancer
Research (August 2010) has shown that ID1 can be used to mark
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Ling F, Kang B, Sun XH (2014). "Id proteins: small molecules, mighty regulators".
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228:"E Proteins and ID Proteins: Helix-Loop-Helix Partners in Development and Disease"
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598:"Id proteins in cell cycle control and cellular senescence"
557:"Id proteins at the cross-road of development and cancer"
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and thus regulate bHLH transcription factors when they
674:"Id genes are essential for early heart formation"
95:Humans express four types of Id proteins (called
17:Inhibitor of DNA-binding/differentiation proteins
555:Lasorella A, Uo T, Iavarone A (December 2001).
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328:"The interactive fly: Extra macrochaetae"
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70:where they function to prevent premature
470:Current Topics in Developmental Biology
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775:Inhibitor+of+Differentiation+Proteins
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596:Zebedee Z, Hara E (December 2001).
505:"The Id proteins and angiogenesis"
482:10.1016/B978-0-12-405943-6.00005-1
66:ID proteins are key regulators of
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281:Cell Death and Differentiation
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741:10.1158/0008-5472.CAN-10-1142
651:10.1016/j.molmed.2006.10.007
639:Trends in Molecular Medicine
358:10.1016/j.molmed.2004.06.008
346:Trends in Molecular Medicine
244:10.1016/j.devcel.2015.10.019
116:endothelial progenitor cells
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379:Yokota Y (December 2001).
226:Wang LH, Baker NE (2015).
27:that heterodimerize with
779:Medical Subject Headings
678:Genes & Development
691:10.1101/gad.300400.117
615:10.1038/sj.onc.1205092
574:10.1038/sj.onc.1205093
522:10.1038/sj.onc.1205160
427:Nature Reviews. Cancer
398:10.1038/sj.onc.1205090
294:10.1038/sj.cdd.4401467
205:10.1006/geno.1995.1026
150:Nature Reviews. Cancer
29:basic helix-loop-helix
33:transcription factors
23:comprise a family of
381:"Id and development"
326:Brody T B (1998).
795:Enzyme inhibitors
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68:development
35:to inhibit
21:ID proteins
789:Categories
304:2297/15884
127:References
76:stem cells
54:is called
51:Drosophila
759:20807818
710:28794185
659:17071138
624:11840324
602:Oncogene
583:11840325
561:Oncogene
531:11840326
509:Oncogene
490:25248477
455:31055227
447:24442143
407:11840321
385:Oncogene
366:15310459
313:15181457
262:26555048
232:Dev Cell
193:Genomics
178:19850793
170:16034366
91:Subtypes
62:Function
25:proteins
750:3058751
701:5580654
539:7533233
253:4684411
213:7665172
84:neurons
31:(bHLH)
781:(MeSH)
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174:S2CID
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620:PMID
579:PMID
527:PMID
486:PMID
443:PMID
403:PMID
362:PMID
309:PMID
258:PMID
209:PMID
166:PMID
745:PMC
737:doi
696:PMC
686:doi
647:doi
610:doi
569:doi
517:doi
478:doi
474:110
435:doi
393:doi
354:doi
299:hdl
289:doi
248:PMC
240:doi
201:doi
158:doi
111:).
109:ID4
105:ID3
101:ID2
97:ID1
74:of
37:DNA
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