Inhibitor of DNA-binding protein
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Inhibitor of DNA-binding/differentiation proteins, also known as ID proteins comprise a family of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s that heterodimerize with
basic helix-loop-helix BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...
(bHLH)
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s to inhibit DNA binding of bHLH proteins. 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. 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 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 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. 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.


Function

ID proteins are key regulators of
development Development or developing may refer to: Arts *Development hell, when a project is stuck in development *Filmmaking, development phase, including finance and budgeting *Development (music), the process thematic material is reshaped * Photograph ...
where they function to prevent premature differentiation of stem cells. 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
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
. 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
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s 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 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.


Subtypes

Humans express four types of Id proteins (called ID1,
ID2 DNA-binding protein inhibitor ID-2 is a protein that in humans is encoded by the ''ID2'' gene. Function The protein encoded by this gene belongs to the inhibitor of DNA binding (ID) family, members of which are transcriptional regulators that ...
,
ID3 ID3 is a metadata container most often used in conjunction with the MP3 audio file format. It allows information such as the title, artist, album, track number, and other information about the file to be stored in the file itself. There are tw ...
, and
ID4 ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesi ...
). A recent publication in Cancer Research (August 2010) has shown that ID1 can be used to mark
endothelial progenitor cell Endothelial progenitor cell (or EPC) is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endot ...
s 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. 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 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.


References


External links

* {{MeshName, Inhibitor+of+Differentiation+Proteins Enzyme inhibitors Protein families