[go: up one dir, main page]
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
9.9
5.1
Journals
Cells
Special Issues
Regulation and Function of the Myc Oncogene
share announcement

Regulation and Function of the Myc Oncogene

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 33258

Special Issue Information

Dear Colleagues,

The MYC proto-oncoproteins, c-MYC, MYCN and MYCL, are structurally and functionally conserved transcription factors of the basic helix–loop–helix leucine zipper (bHLHZip) family. They are part of a complex transcriptional network involving other members of the bHLHZip family, including MAX and the MXD proteins. We have studied these proteins for more than 40 years, but still, there is much to learn. MYC proteins play fundamental roles in cell biology during development and cell division, including the regulation of metabolism, protein synthesis, cell adhesion, senescence, and apoptosis. In addition to specific gene regulation through the activation or repression of target genes, MYC is involved in general transcriptional amplification of already active promoters, leading to primary or secondary mRNA amplification. Furthermore, MYC proteins can mediate transcriptional-independent processes, such as DNA replication or mRNA cap methylation. Importantly, MYC genes are overexpressed, by means of translocation, amplification, increased translation or protein stability, in a wide range of human cancers and are frequently associated to aggressiveness and poor outcome. Several approaches to interfere with MYC activity have been explored, with so far limited applicability in the clinical setting. In this Special Issue of Cells, we aim to collect the current knowledge on this fascinating family of proteins, during health and disease in mammals as well as in other organisms. This includes all aspects of MYC biology, such as gene expression, protein stability and regulation, the manifold effects in cellular processes, and physiological control of stemness and tissue development. There will be a special focus on the pathological effects of MYC deregulation and the opportunities for therapeutic intervention in human disease, mainly cancer but also other MYC-associated syndromes.

We are looking forward to your contribution shedding light on this important and enigmatic protein and hope that together, we will bring the field forward!
Best regards,

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MYC transcriptional network
  • Development, cell cycle, and apoptosis
  • Stemness
  • Cancer
  • Inhibition of MYC

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (4 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Review

27 pages, 2386 KiB  
Review
Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein
by Marie-Eve Beaulieu, Francisco Castillo and Laura Soucek
Cells 2020, 9(4), 1038; https://doi.org/10.3390/cells9041038 - 22 Apr 2020
Cited by 61 | Viewed by 6851
Abstract
Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is [...] Read more.
Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is still surprisingly limited. Indubitably though, its crucial and non-redundant role in cancer biology makes it an attractive target. However, achieving successful clinical Myc inhibition has proven challenging so far, as this nuclear protein is an intrinsically disordered polypeptide devoid of any classical ligand binding pockets. Indeed, Myc only adopts a (partially) folded structure in some contexts and upon interacting with some protein partners, for instance when dimerizing with MAX to bind DNA. Here, we review the cumulative knowledge on Myc structure and biophysics and discuss the implications for its biological function and the development of improved Myc inhibitors. We focus this biophysical walkthrough mainly on the basic region helix–loop–helix leucine zipper motif (bHLHLZ), as it has been the principal target for inhibitory approaches so far. Full article
(This article belongs to the Special Issue Regulation and Function of the Myc Oncogene)
►▼ Show Figures

Figure 1

Figure 1
<p>Timeline highlighting relevant achievements related to MYC biology, pharmacology and biophysics.</p> Full article ">Figure 2
<p>Schematic representation of the modular structure of MYC (UniProtKB code P01106, <a href="https://www.uniprot.org/uniprot/P01106" target="_blank">https://www.uniprot.org/uniprot/P01106</a>). The N-terminal transcription activation domain (TAD, yellow), the central region rich in proline, glutamic acid, serine and tyrosine (PEST, navy blue) and the basic region helix–loop–helix leucine zipper (LZ) domain (bHLHLZ, red) are indicated. The MYC boxes (MB 0-IV) are shown in orange and the nuclear localization sequences (NLS I-II) in cyan. The magnification bubbles show the structural models of MYC fragments (orange for MBs and red for the bHLHLZ) in complex with the interacting partners (light grey) available from the Protein Data Bank (PDB, <a href="https://www.rcsb.org" target="_blank">https://www.rcsb.org</a>) and rendered using Pymol [<a href="#B23-cells-09-01038" class="html-bibr">23</a>]. For the TAD region: 1MVO, in complex with Bin1 [<a href="#B24-cells-09-01038" class="html-bibr">24</a>]; 6E16 in complex with TBP-TAF [<a href="#B25-cells-09-01038" class="html-bibr">25</a>]; 4Y7R in complex with WDR5 [<a href="#B26-cells-09-01038" class="html-bibr">26</a>]. For the bHLHLZ, 6G6L shows the MYC/MAX heterodimer in the absence of DNA [<a href="#B27-cells-09-01038" class="html-bibr">27</a>].</p> Full article ">Figure 3
<p>Schematic representation of the modular structure of p22MAX (MYC-associated factor X protein, UniProtKB code P61244). The naturally occurring (p21MAX) and oncogenic (DeltaMAX) MAX variants are identified. The three phosphorylation sites target of Casein Kinase II (CKII) are identified on MAX by the symbol * [<a href="#B38-cells-09-01038" class="html-bibr">38</a>], both increasing the on- and off-rates of the homo- and heterodimers on DNA in vivo, are indicated by stars. The crystal structure of the DNA-bound p21MAX is displayed on the right. One monomer highlights the Basic Region in dark blue, the Helix-Loop-Helix domain in different shades of blue corresponding to H1, Loop and H2 elements and the Leucine Zipper in purple. The other monomer is shown in white while the double stranded DNA E-box is displayed in black.</p> Full article ">Figure 4
<p>(<b>A</b>). Sequence alignment of the LZ of MYC, MYCL, MYCN, and MAX with heptad-repeat numbering. (<b>B</b>–<b>D</b>). Helical-wheel representation for the interfacial interactions in the LZ domains from MYC and MAX putative dimeric complexes: The MAX/MAX homodimer is shown in panel (<b>B</b>), the putative MYC/MYC homodimer in panel (<b>C</b>) and the MYC/MAX heterodimer in panel (<b>D</b>). The favorable and unfavorable inter-molecular contacts are displayed as arrows. The amino acids are colored blue for positively charge residues, red for negatively charged residues, green for polar residues and black for the remainder apolar residues. Adapted from Lavigne et al. 1995 [<a href="#B40-cells-09-01038" class="html-bibr">40</a>]. (<b>E</b>,<b>F</b>) Molecular models of the tridimensional structure of a putative DNA-bound MYC homodimer (<b>E</b>), of the crystal structure of the MAX homodimer (PDB 1AN2, <b>F</b>) and of the MYC/MAX heterodimer (PDB 1NKP, <b>G</b>). (<b>E</b>). Homology model of a putative MYC/MYC homodimer (the sequence of MYC was superimposed on the MAX structure from 1NKP.pdb) with one monomer shown in red and the other in grey. The inset highlights the highly unfavorable electrostatic repulsions between the clusters of negatively charged interfacial residues Glu409-Glu410, Glu416-Glu417, and Arg423-Arg424 and their respective counterpart on the other monomer are shown with stick representation. Negatively charged residues are shown in red, positively charged residues in blue. F. Crystal structure of the MAX homodimer; the inset evidences the polar residues at interfacial a and d positions, namely Met74, Asn78, His81, Asn92 (shown in cyan stick representation). (<b>G</b>). Crystal structure of the MYC/MAX heterodimer with close up views on the MYC-Leu396/MAX-Phe43 interaction within the HLH (top inset); the Ser373 and Thr400 phosphorylation sites are shown in green (note: Asp65 from MAX, directly facing MYC-Ser373, is shown in red—middle inset); the interfacial, buried interaction between MAX-His81 (cyan) and MYC-Glu410 and Glu417 (in red) is shown (bottom inset).</p> Full article ">Figure 5
<p>(<b>A</b>). Top: Sequence alignment of MYC (red), MYCN, MYCL, and MAX (blue). The binding sites for small molecules (SM) are identified: Site I in cyan, Site II in green and Site III in purple. The secondary structure prediction (SSP) for the MYC bHLHLZ in absence of MAX and of DNA is shown (adapted from Panova et al. [<a href="#B55-cells-09-01038" class="html-bibr">55</a>]): Positive values correspond to helix and negative values indicate β–strand or polyproline II helix (PPII). Filled bars indicate predictions from the measured chemical shifts, while open bars refer to predictions based on signal broadening. Below, the hydrophobicity of the MYC (red) and MAX (blue) polypeptides as calculated from ProtScale using the Kyte and Doolittle reference values (<a href="https://web.expasy.org/protscale/pscale/Hphob.Doolittle.html" target="_blank">https://web.expasy.org/protscale/pscale/Hphob.Doolittle.html</a>). (<b>B</b>). Crystal structure of the DNA-bound MYC/MAX heterodimer (1NKP.pdb) highlighting the binding sites for SM (the same color code as in A is used). (<b>C</b>). Two-dimensional structure of the SM MYC inhibitors mentioned in the manuscript. The SM inhibitors binding to Site I, Site II or Site III are indicated.</p> Full article ">
19 pages, 1362 KiB  
Review
Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc
by Daniel Massó-Vallés and Laura Soucek
Cells 2020, 9(4), 883; https://doi.org/10.3390/cells9040883 - 4 Apr 2020
Cited by 91 | Viewed by 9365
Abstract
First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer [...] Read more.
First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein—following the surprising discovery of its cell-penetrating capacity—constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic. Full article
(This article belongs to the Special Issue Regulation and Function of the Myc Oncogene)
►▼ Show Figures

Figure 1

Figure 1
<p>Omomyc acts as a dominant negative of Myc proteins. (<b>A</b>) Representation of the crystal structure of the MYC/Myc-associated protein X (MAX) dimer (1NKP, left) [<a href="#B12-cells-09-00883" class="html-bibr">12</a>] and Omomyc/Omomyc dimer (5I50, right) [<a href="#B13-cells-09-00883" class="html-bibr">13</a>] basic helix–loop–helix leucine zipper (bHLHLZ)-bound to DNA. Square boxes show a higher magnification of the basic region of MYC (left) and Omomyc (right) bound to a consensus E-box, with base-specific interactions as dotted black lines. PyMOL [<a href="#B14-cells-09-00883" class="html-bibr">14</a>] was used to generate these representations. (<b>B</b>) Comparison between the sequences of MYC, Omomyc and the MAX leucine zipper. Residues that mediate the specific interaction of the basic region with DNA bases are colored in red, residues forming the hydrophobic core of the leucine zippers are colored in orange and the four mutated residues in Omomyc are colored in green. Below, a schematic representation of the MYC, Omomyc, and MAX proteins is shown. Asterisks represent the four mutated amino acids in Omomyc. (<b>C</b>) Representation of the interactions between MYC, MAX and Omomyc and their binding to DNA. When Omomyc is absent, MYC heterodimerizes with MAX and they together bind E-box sequences on the DNA, where MYC induces transcription of its target genes (left panel). When Omomyc (OMO) is present, it heterodimerizes with MYC sequestering it away from DNA, while also forming transcriptionally inactive homodimers and heterodimers with MAX that occupy E-boxes, resulting in inhibition of transcription of MYC targets (right panel). b: basic region. HLH: helix–loop–helix. LZ: leucine zipper. TAD: transactivation domain. MBI-IV: Myc boxes I-IV.</p> Full article ">Figure 2
<p>Expression of the Omomyc transgene has remarkable therapeutic impact in 5 different genetically engineered mouse models of cancer, from left to right: papilloma, <span class="html-italic">inv-Myc-ER<sup>TAM</sup></span> (top panel) and <span class="html-italic">inv-Myc-ER<sup>TAM</sup>/Omomyc</span> (bottom panel), adapted from [<a href="#B56-cells-09-00883" class="html-bibr">56</a>]; insulinoma, <span class="html-italic">RIP1-Tag2</span>;<span class="html-italic">TRE-Omomyc;CMV-rtTA</span> -dox (top) and +dox (bottom), adapted from [<a href="#B70-cells-09-00883" class="html-bibr">70</a>]; lung adenocarcinoma, <span class="html-italic">LSL-Kras<sup>G12D</sup></span>;<span class="html-italic">p53ER<sup>TAM</sup>;TRE-Omomyc;CMV-rtTA</span> -dox (top) and +dox (bottom), adapted from [<a href="#B71-cells-09-00883" class="html-bibr">71</a>]; glioma, <span class="html-italic">GFAP-<sup>V12</sup>Ha-Ras;TRE-Omomyc;CMV-rtTA</span> -dox (top) and +dox (bottom) adapted from [<a href="#B67-cells-09-00883" class="html-bibr">67</a>]; and pancreatic ductal adenocarcinoma, <span class="html-italic">pdx1-Cre;LSL-KRas<sup>G12D</sup>;p53ER<sup>TAM</sup>;TRE-Omomyc;CMV-rtTA</span> -dox (top) and +dox (bottom), adapted from [<a href="#B72-cells-09-00883" class="html-bibr">72</a>]. All panels represent tissue sections stained with either an anti-GFAP antibody (glioma) or with hematoxylin and eosin (rest of the panels). Pancreatic islets in the insulinoma panels are circled with a dotted yellow line.</p> Full article ">
16 pages, 1046 KiB  
Review
The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias
by Raffaella Pippa and Maria D. Odero
Cells 2020, 9(3), 544; https://doi.org/10.3390/cells9030544 - 26 Feb 2020
Cited by 22 | Viewed by 5373
Abstract
The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and [...] Read more.
The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias. Full article
(This article belongs to the Special Issue Regulation and Function of the Myc Oncogene)
►▼ Show Figures

Figure 1

Figure 1
<p>MYC regulation by PP2A. MYC undergoes two critical phospho-modifications on S62 and T58 residues. The phosphorylation on T58 is regulated by GSK3β. To be active, GSK3β has to be dephosphorylated. The PP2A complex, which includes the B56α subunit, dephosphorylates and activates GSK3β. Interestingly, the B56α subunit is transcriptionally activated by MYC. Moreover, the presence of a phosphorylated T58 residue also recruits the PP2A-B56α complex, which dephosphorylated the S62 phospho-residue. Dephosphorylation of S62 residue eventually targets MYC for ubiquitin-mediated proteosomal degradation. See text for more details.</p> Full article ">Figure 2
<p>MYC/PP2A inhibitory network. MYC transcriptionally regulates SET and CIP2A. SET binds to the PP2A-C subunit, while CIP2A interacts with PP2A-B56???? subunit. Their increased expressions lead to PP2A inhibition in leukemia cells. SETBP1 is a SET binding protein overexpressed in myeloid leukemias that prevents SET cleavage. ARPP19 is another inhibitor of PP2A that has been recently reported to enhance the levels of CIP2A, SET, and MYC in AML.</p> Full article ">
24 pages, 1105 KiB  
Review
MYC’s Fine Line Between B Cell Development and Malignancy
by Oriol de Barrios, Ainara Meler and Maribel Parra
Cells 2020, 9(2), 523; https://doi.org/10.3390/cells9020523 - 24 Feb 2020
Cited by 21 | Viewed by 10767
Abstract
The transcription factor MYC is transiently expressed during B lymphocyte development, and its correct modulation is essential in defined developmental transitions. Although temporary downregulation of MYC is essential at specific points, basal levels of expression are maintained, and its protein levels are not [...] Read more.
The transcription factor MYC is transiently expressed during B lymphocyte development, and its correct modulation is essential in defined developmental transitions. Although temporary downregulation of MYC is essential at specific points, basal levels of expression are maintained, and its protein levels are not completely silenced until the B cell becomes fully differentiated into a plasma cell or a memory B cell. MYC has been described as a proto-oncogene that is closely involved in many cancers, including leukemia and lymphoma. Aberrant expression of MYC protein in these hematological malignancies results in an uncontrolled rate of proliferation and, thereby, a blockade of the differentiation process. MYC is not activated by mutations in the coding sequence, and, as reviewed here, its overexpression in leukemia and lymphoma is mainly caused by gene amplification, chromosomal translocations, and aberrant regulation of its transcription. This review provides a thorough overview of the role of MYC in the developmental steps of B cells, and of how it performs its essential function in an oncogenic context, highlighting the importance of appropriate MYC regulation circuitry. Full article
(This article belongs to the Special Issue Regulation and Function of the Myc Oncogene)
►▼ Show Figures

Figure 1

Figure 1
<p>Expression and role of MYC in B lymphocyte differentiation. Schematic representation of the participation of the MYC protein throughout B-cell differentiation in the bone marrow and germinal center (GC). The percentages shown refer to the population of MYC<sup>+</sup>, BCL6<sup>+/−</sup> cells in the total number of B cells present in the GC. The blue-colored line at the top of the Figure indicates the evolution of MYC expression, where darker blue indicates steps that require higher MYC levels.</p> Full article ">Figure 2
<p>Activating mechanisms of c-MYC in leukemia with the BCR-ABL1 rearrangement. A summary of the different transduction signaling pathways that trigger the activation of MYC promoter in BCR-ABL1-rearranged leukemia. Apart from direct transcriptional activation pathways, marked in green, alternative mechanisms that induce c-MYC are depicted in black and highlighted in black squares. Dashed arrows indicate the translocation of proteins between the nucleus and the cytoplasm.</p> Full article ">
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-4
Back to TopTop