Inhibitor of DNA-binding protein

Inhibitor of DNA-binding/differentiation proteins, also known as ID proteins comprise a family of proteins that heterodimerize with basic helix-loop-helix (bHLH) transcription factors to inhibit DNA binding of bHLH proteins.[1] ID proteins also contain the HLH-dimerization domain but lack the basic DNA-binding domain and thus regulate bHLH transcription factors when they heterodimerize with bHLH proteins.[2] The first helix-loop-helix proteins identified were named E-proteins because they bind to Ephrussi-box (E-box) sequences.[3] In normal development, E proteins form dimers with other bHLH transcription factors, allowing transcription to occur. However, in cancerous phenotypes, ID proteins can regulate transcription by binding E proteins, so no dimers can be formed and transcription is inactive.[1] E proteins are members of the class I bHLH family and form dimers with bHLH proteins from class II to regulate transcription.[4] Four ID proteins exist in humans: ID1, ID2, ID3, and ID4. The ID homologue gene in Drosophila is called extramacrochaetae (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.[5] 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.[6] 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.[6]

Function

ID proteins are key regulators of development where they function to prevent premature differentiation of stem cells.[7] By inhibiting the formation of E-protein dimers that promote differentiation, ID proteins can regulate the timing of differentiation of stem cells during development.[8] 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.[9] In contrast, inappropriate regulation of ID proteins in differentiated cells can contribute to tumorigenesis.[10][11][12] Generally, IDs function as oncogenes. When ID proteins are overexpressed, cell proliferation is enhanced and cells become insensitive to growth factor depletion.[11] Expression of ID proteins in neurons halts neuron axon growth and allows elongation of neurons.[13] Knockout mouse data show that ID genes are essential for heart development.[14] There is some controversy surrounding the ID proteins and their role in cancer, but overexpression is seen in most tumor types.[8] There are a few exceptions, for 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.[8] ID proteins can bind E-proteins, preventing them from binding bHLH proteins and halting transcription, a case often seen in cancerous phenotypes.[1]

Subtypes

Humans express four types of Id proteins (called ID1, ID2, ID3, and ID4).

A recent publication in Cancer Research (August 2010) has shown that ID1 can be used to mark endothelial progenitor cells 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.[15]

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.[1] 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 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.[1]

References
  1. Perk J, Iavarone A, Benezra R (August 2005). "Id family of helix-loop-helix proteins in cancer". Nature Reviews. Cancer. 5 (8): 603–14. doi:10.1038/nrc1673. PMID 16034366. S2CID 19850793.
  2. 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". Genomics. 27 (1): 200–3. doi:10.1006/geno.1995.1026. PMID 7665172.
  3. Wang LH, Baker NE (2015). "E Proteins and ID Proteins: Helix-Loop-Helix Partners in Development and Disease". Dev Cell. 35 (3): 269–80. doi:10.1016/j.devcel.2015.10.019. PMC 4684411. PMID 26555048.
  4. Kondo M, Cubillo E, Tobiume K, Shirakihara T, Fukuda N, Suzuki H, Shimizu K, Takehara K, Cano A, Saitoh M, Miyazono K (October 2004). "A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation". Cell Death and Differentiation. 11 (10): 1092–101. doi:10.1038/sj.cdd.4401467. PMID 15181457.
  5. Brody T B (1998). "The interactive fly: Extra macrochaetae".
  6. Fong S, Debs RJ, Desprez PY (August 2004). "Id genes and proteins as promising targets in cancer therapy". Trends in Molecular Medicine. 10 (8): 387–92. doi:10.1016/j.molmed.2004.06.008. PMID 15310459.
  7. Yokota Y (December 2001). "Id and development". Oncogene. 20 (58): 8290–8. doi:10.1038/sj.onc.1205090. PMID 11840321.
  8. Lasorella A, Benezra R, Iavarone A (February 2014). "The ID proteins: master regulators of cancer stem cells and tumour aggressiveness". Nature Reviews. Cancer. 14 (2): 77–91. doi:10.1038/nrc3638. PMID 24442143. S2CID 31055227.
  9. Ling F, Kang B, Sun XH (2014). "Id proteins: small molecules, mighty regulators". Current Topics in Developmental Biology. 110: 189–216. doi:10.1016/B978-0-12-405943-6.00005-1. PMID 25248477.
  10. Benezra R, Rafii S, Lyden D (December 2001). "The Id proteins and angiogenesis". Oncogene. 20 (58): 8334–41. doi:10.1038/sj.onc.1205160. PMID 11840326. S2CID 7533233.
  11. Lasorella A, Uo T, Iavarone A (December 2001). "Id proteins at the cross-road of development and cancer". Oncogene. 20 (58): 8326–33. doi:10.1038/sj.onc.1205093. PMID 11840325.
  12. Zebedee Z, Hara E (December 2001). "Id proteins in cell cycle control and cellular senescence". Oncogene. 20 (58): 8317–25. doi:10.1038/sj.onc.1205092. PMID 11840324.
  13. Iavarone A, Lasorella A (December 2006). "ID proteins as targets in cancer and tools in neurobiology". Trends in Molecular Medicine. 12 (12): 588–94. doi:10.1016/j.molmed.2006.10.007. PMID 17071138.
  14. Cunningham TJ, Yu MS, McKeithan WL, Spiering S, Carrette F, Huang CT, et al. (July 2017). "Id genes are essential for early heart formation". Genes & Development. 31 (13): 1325–1338. doi:10.1101/gad.300400.117. PMC 5580654. PMID 28794185.
  15. 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). "Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth". Cancer Research. 70 (18): 7273–82. doi:10.1158/0008-5472.CAN-10-1142. PMC 3058751. PMID 20807818.
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