Myc target protein 1 (MYCT1) is regulated by the c-Myc oncoprotein; its promoter is a direct c-Myc target. Furthermore, MYCT1 regulates the expression of several other c-Myc target genes [].
The class III basic helix-turn-helix (bHLH) transcription factors have proliferative and apoptotic roles and are characterised by the presence of a leucine zipper adjacent to the bHLH domain. The myc oncogene was first discovered in small-cell lung cancer cell lines where it is found to be deregulated []. The Myc protein contains an N-terminal transcriptional regulatory domain followed by a nuclear localization signal and a C-terminal basic DNA binding domain tethered to a helix-loop-helix-leucine zipper (HLH-Zip) dimerization motif. Myc forms a heterodimer with Max, and this complex regulates cell growth through direct activation of genes involved in cell replication [, , ].The `leucine zipper' is a structure that is believed to mediate the function of several eukaryotic gene regulatory proteins. The zipper consists of a periodic repetition of leucine residues at every seventh position, and regions containing them appear to span eight turns of α-helix. The leucine side chains that extend from one helix interact with those from a similar helix, hence facilitating dimerisation in the form of a coiled-coil. Leucine zippers are present in many gene regulatory proteins, including the CREB proteins, Jun/AP1 transcription factors, fos oncogene and fos-related proteins, C-myc, L-myc and N-myc oncogenes, and so on.
This family consists of the leucine zipper dimerisation domain found in both cellular c-Myc proto-oncogenes and viral v-Myc oncogenes. Dimerisation via the leucine zipper motif with other basic helix-loop-helix-leucinezipper (b/HLH/lz) proteins is required for efficient DNA binding []. The Myc-Maxdimer is a transactivating complex activating expression of growth related genes promoting cell proliferation.The dimerisation is facilitated via interdigitating leucine residues every 7th position of the alpha helix. Likecharge repulsion of adjacent residues in this region preturbs the formation of homodimers with heterodimersbeing promoted by opposing charge attractions. It has been demonstrated that in transgenic mice the balance between oncogene-induced proliferation and apoptosis in a given tissue can be a critical determinant in the initiation and maintenance of the tumor [].
This is the N-terminal region of a family of MYB and MYC transcription factors. The DNA-binding HLH domain is further downstream, . Members of the MYB and MYC family regulate the biosynthesis of phenylpropanoids in several plant species [, ].
MXD1, also known as MAD, binds Max to form a repressive transcription factor. It antagonizes MYC transcriptional activity by competing for MAX []. It has also been shown to regulate rRNA synthesis [].
Cell division cycle-associated protein 7 (CDCA7/JPO1) is a transcription regulator whose expression is activated by c-Myc and by E2F1 []. CDCA7 can associate with Myc in a phosphorylation-dependent manner. CDCA7 phosphorylation by AKT leads to loss of its association with Myc []. This interaction affects Myc-dependent apoptosis and transformation [, , ]. CDCA7 has also been identified as a Notch target involved in hematopoietic stem cell emergence [].
This entry represents a domain found in the C terminus of Far upstream element-binding protein 1/2 (FUBP1/2) []. FUBP1 regulates MYC expression by binding to a single-stranded far-upstream element (FUSE) upstream of the MYC promoter [, ]. FUBP2, also known as KSRP (K homology-type splicing regulatory protein), is an single-strand-RNA binding protein that integrate different levels of gene expression and is required for proper immune response, lipid metabolism, cell fate decisions, and tissue regeneration [].
YY1-associated factor 2 (YAF2) binds to MYC and MYCN, inhibiting MYC-mediated transactivation and enhances MYCN-dependent transcriptional activation [, ]. It interacts with YY1, which is down-regulated at the protein level during myogenic differentiation, enhancing its degradation by calpain 2 []. It is a component of the E2F6.com-1 complex in G0 phase of the cell cycle []. YAF2 contains a RanBP2-type zinc finger.
This entry represents heterogeneous nuclear ribonucleoprotein U (hnRNP U). hnRNP U is a component of the CRD-mediated complex that promotes MYC mRNA stabilisation. It binds to pre-mRNA. It has high affinity for scaffold-attached region (SAR) DNA. It binds to double and single strand DNA and RNA [].
This entry represents the DEAD-box helicase domain found in DDX18 from animals and Has1 from fungi. This domain contains the ATP-binding region. Has1 is a ATP-dependent RNA helicase involved in 40S and 60S ribosomal subunit biogenesis [, ]. DDX18 is a putative RNA-dependent helicase which is activated by Myc protein [].
MAX gene-associated protein (MGA) is a dual-specificity transcription factor, acting as a repressor or an activator and binding to 5'-AATTTCACACCTAGGTGTGAAATT-3'. MGA regulates genes targeted by MYC-MAX, suppressing transcriptional activation by MYC and inhibiting MYC-dependent cell transformation. MGA binds DNA via a T-Box []. MGA is a component of the MLL1 complex [].
The class III basic helix-turn-helix (bHLH) transcription factors have proliferative and apoptotic roles and are characterised by the presence of a leucine zipper adjacent to the bHLH domain. The myc oncogene gene was first discovered in small-cell lung cancer cell lines where it is found to be deregulated []. Although the biochemical function of the gene product is unknown, as a nuclear protein with a short half-life it may play a direct or indirect role in controlling gene expression []. Myc forms a heterodimer with Max, and this complex regulates cell growth through direct activation of genes involved in cell replication [].This entry represents the N-terminal domain found adjacent to the basic helix-loop-helix (bHLH) region ().
Proteins included in this entry have an N-terminal RanBP2-type zinc finger and a Yaf2/RYBP C-terminal binding motif. Proteins with these regions include Yaf2 and RYBP proteins, which are homologous parts of the PRC1 complex [].RYBP is a zinc finger protein with an essential role during embryonic development, which binds transcriptional factors, Polycomb products, and mediators of apoptosisis []. RYBP also binds ubiquitin and Cbx proteins via the C-terminal docking module [, ]. RYBP is natively unstructured until it binds to the C-terminal region of the Polycomb protein Ring1B or to DNA []. Yaf2 binds to MYC and inhibits MYC-mediated transactivation [].
This domain can be found in the MAX gene-associated protein (Mga), which is a dual-specificity transcription factor that contains both a bHLHZip domain and a T-box domain and is able to bind to and regulate transcriptional targets through both E-box sites as well as T-box-binding elements (TBEs) []. MAX gene-associated protein (MGA) is a dual-specificity transcription factor, acting as a repressor or an activator and binding to 5'-AATTTCACACCTAGGTGTGAAATT-3'. MGA regulates genes targeted by MYC-MAX, suppressing transcriptional activation by MYC and inhibiting MYC-dependent cell transformation. MGA binds DNA via a T-Box []. MGA is a component of the MLL1 complex [].
This family represents the periodic tryptophan protein 1 (PWP1), a chromatin-associated factor that regulates transcription during developmental growth as part of the TORC1 and Myc signaling pathway in response to nutrients. It regulates Pol I-mediated rRNA biogenesis and the epigenetic status of rDNA []. Drosophila melanogaster PWP1, also known as Protein no child left behind (nclb), is required in males for both germline stem cell (GSC) maintenance and early stages of germ cell differentiation of germ cell cysts []. In females it is necessary to regulate germ cell differentiation and egg chamber development [].
Sin3a is a transcriptional repressor and a homologue of the SIN3 repressor from yeast. Sin3a associates with the strong repressive isoform of Mxi1, a helix-loop-helix leucone zipper that associates with Max to antagonize Myc oncogenic activities []. Unlike Mxi1 and Myc, expression of Sin3a does not vary during development []. Sin3a is a component of several complexes, including the REST-CoREST repressor complex [], the PER complex which maintains circadian rhythm []and the Sin3 HDAC complex []. Sin3a also interacts with FOXK1 to regulate cell cycle progression []. Sin3a has three PAH domains by which it interacts with HCFC1, REST and SAP30 [, ].
This is the N-terminal domain found in Zmiz1 proteins (Zinc finger MIZ domain-containing protein 1). Zmiz1 is a direct Notch1 cofactor that heterogeneously regulates Notch target genes. Zmiz1 directly interacts with the RAM1 domain of Notch1 through this N-terminal tetratricopeptide repeat (TPR) domain. Furthermore, it has been shown that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the N-terminal TPR domain resulting in a slight increase in activating histone marks and decrease of repressive histone marks. Functional analysis indicate that the N-terminal Domain of Zmiz1 is important for driving Myc transcription and proliferation indirectly [].
This entry includes several bHLH transcription factors from plants, such as AIB and MYC proteins (MYC2, MYC3 and MYC4). AIB, also termed AtbHLH17, or EN 35, is a transcription activator that regulates positively abscisic acid (ABA) response []. MYC2, also termed protein jasmonate insensitive 1, is a transcriptional activator involved in abscisic acid (ABA), jasmonic acid (JA), and light signaling pathways [, , , ]. MYC3 is a transcription factor involved in tryptophan, jasmonic acid (JA) and other stress-responsive gene regulation []. MYC4 is a transcription factor involved in jasmonic acid (JA) gene regulation. MYC2, together with MYC3 and MYC4, controls additively subsets of JA-dependent responses [, ].
This motif is found in the C-terminal region of the Yaf2 and RYBP proteins, which are homologous parts of the PRC1 complex [].RYBP is a zinc finger protein with an essential role during embryonic development, which binds transcriptional factors, Polycomb products, and mediators of apoptosisis []. RYBP also binds ubiquitin and Cbx proteins via the C-terminal docking module [, ]. RYBP is natively unstructured until it binds to the C-terminal region of the Polycomb protein Ring1B or to DNA []. Yaf2 binds to MYC and inhibits MYC-mediated transactivation [].
This entry includes CDCA7 and CDA7L.Cell division cycle-associated protein 7 (CDCA7/JPO1) is a transcription regulator whose expression is activated by c-Myc and by E2F1 []. CDCA7 can associate with Myc in a phosphorylation-dependent manner. CDCA7 phosphorylation by AKT leads to loss of its association with Myc []. This interaction affects Myc-dependent apoptosis and transformation [, , ]. CDCA7 has also been identified as a Notch target involved in hematopoietic stem cell emergence [].Cell division cycle-associated 7-like protein (CDCA7L/JPO2/R1) is closely related to CDCA7/JPO1; and like CDCA7, it plays a role in transcriptional regulation and interacts with c-Myc []. JPO2 overexpression induces metastasis in medulloblastoma []. JPO2 can interact directly and dynamically with chromatin, the dynamics of JPO2 chromatin binding being decelerated upon interaction with LEDGF/p75, which binds and tethers JPO2 to chromatin [, ].JPO2 inhibits monoamine oxidase A (MAOA) activity and gene expression by binding to the promoter []. JPO2 and MAOA act upstream of cyclin D1 and E2F1, and are involved in apoptotic signalling pathways [].
This family includes 3-phosphoinositide-dependent protein kinase 1 (PDK1 or PDPK1) and related kinases from yeast: Pkh1 and Pkh2 from S. cerevisiae, which function similarly to PDK1 [], and Ksg1 []and Ppk21 from S. pombe [].PDK1 is the kinase responsible for the phosphorylation of PKB/Akt on the activation loop, at threonine 308, which is essential for Akt activation [, ]. Beyond Akt, PDK1 is responsible for the phosphorylation of many other AGC kinases including serum/glucocorticoid regulated kinase (SGK) []and the members of protein kinase C (PKC) family []. PDK1 is implicated in signaling pathways frequently altered in cancer, such as PI3K/Akt, Ras/MAPK and Myc []. It is a key regulator of cell migration and tumor invasion []. PDK1 binds to the insulin receptor, followed by tyrosine phosphorylation of PDK1 by the insulin receptor, which is necessary for insulin metabolic signaling []. Deficiency of PDK1 in liver results in glucose intolerance [].
In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc, and the Polycomb module represses developmental genes []. This family includes the polycomb repressive complex 2-associated factor EPOP (Elongin BC and Polycomb Repressive Complex 2 (PRC2) Associated Protein, also termed C17orf96, esPRC2p48, E130012A19Rik), a scaffold protein expressed in the inner cell mass of the mouse blastocyst serving as a bridging partner between the PRC2/EED-EZH2 complex and the elongin BC complex, and fine-tuning the transcriptional status of Polycomb group (PcG) target genes in embryonic stem cells. Both EPOP and Elongin BC are required to maintain low levels of expression at PRC2 genomic targets []. EPOP interacts with the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC [].Another member of the family is the uncharacterized SKI/DACH domain-containing protein 1.
Protein max is a transcription regulator that forms a complex with MYC or MAD []. The MYC:MAX complex is a transcriptional activator, whereas the MAD:MAX complex is a repressor. MAX is also a component of the E2F6.com-1 []and MLL1 complexes []. Mutations in the MAX gene are associated with hereditary pheochromocytoma, which is a tumour of the chromaffin tissue of the adrenal medulla or sympathetic paraganglia resulting in hypertension [].This entry also includes Mxl-1 and Mxl-3 from Caenorhabditis elegans. Mxl-1 forms complexes with Mdl1. The Mdl-1:Mxl-1 complex functions in both the insulin signaling and dietary restriction pathways and is involved in the control of lifespan in response to dietary restriction []. Mxl-3 is a transcription factor that modulates the inhibition of lipolysis. It also regulates lipid metabolism during nutritional excess [].
A number of eukaryotic proteins, which probably are sequence specific DNA-binding proteins that act as transcription factors, share a conserved domain of 40 to 50 amino acid residues. It has been proposed []that this domain is formed of two amphipathic helices joined by a variable length linker region that could form a loop. This 'helix-loop-helix' (HLH) domain mediates protein dimerization and has been found in the proteins listed below []. Most of these proteins have an extra basic region of about 15 amino acid residues that is adjacent to the HLH domain and specifically binds to DNA. They are referred as basic helix-loop-helix proteins (bHLH), and are classified in two groups: class A (ubiquitous) and class B (tissue-specific). Members of the bHLH family bind variations on the core sequence 'CANNTG', also referred to asthe E-box motif. The homo- or heterodimerization mediated by the HLH domain is independent of, but necessary for DNA binding, as two basic regions are required for DNA binding activity. The HLH proteins lacking the basic domain (Emc, Id) function as negative regulators, since they form heterodimers, but fail to bind DNA. The hairy-related proteins (hairy, E(spl), deadpan) also repress transcription although they can bind DNA. The proteins of this subfamily act together with co-repressor proteins, like groucho, through their -terminal motif WRPW.Proteins containing a HLH domain include:The myc family of cellular oncogenes [], which is currently known to contain four members: c-myc, N-myc, L-myc, and B-myc. The myc genes are thought to play a role in cellular differentiation and proliferation.Proteins involved in myogenesis (the induction of muscle cells). In mammals MyoD1 (Myf-3), myogenin (Myf-4), Myf-5, and Myf-6 (Mrf4 or herculin), in birds CMD1 (QMF-1), in Xenopus MyoD and MF25, in Caenorhabditis elegans CeMyoD, and in Drosophila nautilus (nau).Vertebrate proteins that bind specific DNA sequences ('E boxes') in various immunoglobulin chains enhancers: E2A or ITF-1 (E12/pan-2 and E47/pan-1), ITF-2 (tcf4), TFE3, and TFEB.Vertebrate neurogenic differentiation factor 1 that acts as differentiation factor during neurogenesis.Vertebrate MAX protein, a transcription regulator that forms a sequence- specific DNA-binding protein complex with myc or mad.Vertebrate Max Interacting Protein 1 (MXI1 protein) which acts as a transcriptional repressor and may antagonize myc transcriptional activity by competing for max.Proteins of the bHLH/PAS superfamily which are transcriptional activators. In mammals, AH receptor nuclear translocator (ARNT), single-minded homologues (SIM1 and SIM2), hypoxia-inducible factor 1 alpha (HIF1A), AH receptor (AHR), neuronal pas domain proteins (NPAS1 and NPAS2), endothelial pas domain protein 1 (EPAS1), mouse ARNT2, and human BMAL1. In Drosophila, single-minded (SIM), AH receptor nuclear translocator (ARNT), trachealess protein (TRH), and similar protein (SIMA).Mammalian transcription factors HES, which repress transcription by acting on two types of DNA sequences, the E box and the N box.Mammalian MAD protein (max dimerizer) which acts as transcriptional repressor and may antagonize myc transcriptional activity by competing for max.Mammalian Upstream Stimulatory Factor 1 and 2 (USF1 and USF2), which bind to a symmetrical DNA sequence that is found in a variety of viral and cellular promoters.Human lyl-1 protein; which is involved, by chromosomal translocation, in T- cell leukemia.Human transcription factor AP-4.Mouse helix-loop-helix proteins MATH-1 and MATH-2 which activate E box- dependent transcription in collaboration with E47.Mammalian stem cell protein (SCL) (also known as tal1), a protein which may play an important role in hemopoietic differentiation. SCL is involved, by chromosomal translocation, in stem-cell leukemia.Mammalian proteins Id1 to Id4 []. Id (inhibitor of DNA binding) proteins lack a basic DNA-binding domain but are able to form heterodimers with other HLH proteins, thereby inhibiting binding to DNA.Drosophila extra-macrochaetae (emc) protein, which participates in sensory organ patterning by antagonizing the neurogenic activity of the achaete- scute complex. Emc is the homologue of mammalian Id proteins.Human Sterol Regulatory Element Binding Protein 1 (SREBP-1), a transcriptional activator that binds to the sterol regulatory element 1 (SRE-1) found in the flanking region of the LDLR gene and in other genes.Drosophila achaete-scute (AS-C) complex proteins T3 (l'sc), T4 (scute), T5 (achaete) and T8 (asense). The AS-C proteins are involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system.Mammalian homologues of achaete-scute proteins, the MASH-1 and MASH-2 proteins.Drosophila atonal protein (ato) which is involved in neurogenesis.
The anaphase-promoting complex (APC) or cyclosome is a multi-subunit E3 protein ubiquitin ligase that regulates important events in mitosis, such as the initiation of anaphase and exit from telophase. The APC, in conjunction with other enzymes, assembles multi-ubiquitin chains on a variety of regulatory proteins, thereby targeting them for proteolysis by the 26S proteasome [].One of the subunits of the APC that is required for ubiquitination activity is APC10, a one-domain protein homologous to a sequence element, termed the DOC domain, found in several hypothetical proteins that may also mediate ubiquitination reactions, because they contain combinations of either RING finger (see ), cullin (see ) or HECT (see ) domains [, , ].The DOC domain consists of a β-sandwich, in which a five-stranded antiparallel β-sheet is packed on top of a three stranded antiparallel β-sheet, exhibiting a 'jellyroll' fold [, ].Proteins known to contain a DOC domain include:Eucaryotic Doc1/Apc10.Mammalian protein associated with the transcription factor Myc (PAM).Mouse runty-jerky-sterile (RJS) protein.Human HERC2, the ortholog of RJS.
Tom1 (target of Myb 1) and its related proteins (Tom1L1 and Tom1L2) constitute a protein family and share an N-terminal VHS (Vps27p/Hrs/Stam) domain followed by a GAT (GGA and Tom1) domain.VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localized to membranes. The three dimensional structure of human TOM1 VHS domain reveals eight helices arranged in a superhelix. The surface of the domain has two main features: (1) a basic patch on one side due to several conserved positively charged residues on helix 3 and (2) a negatively charged ridge on the opposite side, formed by residues on helix 2 []. The basic patch is thought to mediate membrane binding.It was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVB) []. Moreover, Tom1L1 interacts with members of the MVB sorting machinery. Specifically, the VHS domain of Tom1L1 interacts with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domains of Tom1L1, is responsible for binding to TSG101 (tumour susceptibility gene 101). Myc epitope-tagged Tom1L1 is recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signalling proteins such as Grb2 and p85. Expression of a constitutively active form of Fyn kinase promotes the recruitment of Tom1L1 to enlarged endosomes. It is proposed that Tom1L1 could act as an intermediary between the signalling and degradative pathways [].Over expression of Tom1 suppresses activation of the transcription factors NF-kappaB and AP-1, induced by either IL-1beta or tumour necrosis factor (TNF)-alpha, and the VHS domain of Tom1 is indispensable for this suppressive activity. This suggests that Tom1 is a common negative regulator of signalling pathways induced by IL-1beta and TNF-alpha [].
