Figure 4 - available via license: Creative Commons Attribution-NonCommercial 3.0 Unported
Content may be subject to copyright.
Model for c-Myc function. High levels of c-Myc cannot saturate functional c-Myc binding sites (1). After binding c-Myc can be converted into its "active" form (2). The active form of c-Myc is unstable and degraded or removed/inactivated 24,25 by other mechanisms (3).
Source publication
The proto-oncogene c-myc encodes a basic helix-loop-helix leucine zipper transcription factor (c-Myc). c-Myc plays a crucial role in cell growth and proliferation. Here, we examined how expression of c-Myc target genes and cell proliferation depend on variation of c-Myc protein levels. We show that proliferation rates, the number of cells in S-phas...
Contexts in source publication
Context 1
... of total RNA and hybridization of arrays. Labeling, hybridization, scanning and data processing proce- dures were performed as described elsewhere. 26 In brief, a standard It's also unclear whether binding of c-Myc to a bona fide bind- ing site is sufficient for gene activation, or whether c-Myc has to undergo additional modifications/alterations at a binding site to gain its gene regulatory activity. c-Myc is highly modified by phosphorylation, acetylation, and ubiquitinylation. 17,18 If specific modifications are required, c-Myc binding sites can in principal accommodate "inactive" and "active" forms of c-Myc (Fig. 4). In this scenario c-Myc may bind as an "inactive" precursor and must be converted into an "active" form, before it facilitates gene regulation. The transition of c-Myc from the "inactive" into the "active" state could be regulated in a target site-specific manner. However, currently little is known about the specificity of such a process and how efficiently it could ...
Context 2
... is a very short-lived molecule with a half-life of 15-30 min in all phases of the cell cycle except mitosis. 3 This insta- bility, which c-Myc shares with other transcription factors, has been implicated in its gene regulatory function. The removal of "active" c-Myc from its binding site may be accomplished by ubiquitinylation-coupled degradation. Since ubiquitinylation of c-Myc's transactivation domain has also been reported to be a possible mechanism for its conversion into the "active" form, [19][20][21] activation and degradation of c-Myc may be coupled processes occurring as consecutive steps at the target site (see model in Fig. 4). Alternatively, the activation signal may be removed from the "active" form and c-Myc returns to the "inactive" pool. If c-Myc requires an activation mechanism at its target site, this could be an additional rate-limiting step in gene activation. In this case, c-Myc binds to the target site with high or low affin- ity, but gene activation does not occur as long as c-Myc is not converted into its "active" form. Alternatively, c-Myc is directly ...
Similar publications
The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo continuous proliferation; therefore, nucleolar activity i...
Citations
... Overexpression of MYC in quiescent cells will cause cells to re-enter the cell cycle, while inhibiting MYC expression will cause cells in the cell cycle to exit. 48 In our research, the RNA-seq of COQ2 knockout myeloma cells focused on the MYC signalling pathway, regulating multiple MCMs molecular and PCNA expression. Consistent with the cell cycle arrest caused by COQ2 deficient, we confirmed the decreased expression of MYC target genes in both MM1s and H929 cells. ...
Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome‐wide CRISPR‐Cas9 loss‐of‐function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2‐deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4‐CBA enhanced the sensitivity to RSL3 in primary CD138⁺ myeloma cells and in a xenograft mouse model. Nevertheless, co‐treatment of 4‐CBA and RSL3 induced cell death in bortezomib‐resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.
... 7 Notably, MAX forms heterodimers with both transcriptional activators and repressors, and there is an additional protein homologous to MAX, MLX (Max-like protein x), 8 c-MYC was thought to regulate transcription solely via its Transactivation Domain (TAD) at the E-box-containing promoters of target genes. 12 However, this dogma has been challenged over the years, [13][14][15][16] revealing a more complex dynamic of c-MYC function at promoters. Our study of the sole MYC/Mondo family representative in C. elegans, MML-1, demonstrates that its binding to DNA is not sufficient to exert an effect on the transcription of target genes and that an additional regulatory step must be required. ...
... 17 This work is consistent with an earlier study of transcription activation in response to a controlled increase in cellular c-MYC levels that did not show saturation at high c-MYC concentrations and suggested a model whereby c-MYC binding to promoters was not a rate-limiting step in gene regulation. 14 This study proposed that c-MYC gets activated subsequently to promoter binding and that the activated form of c-MYC dissociates from promoters rapidly, likely by being degraded. 14 Indeed, further research may aid with its subsequent degradation by the nuclear proteasome to maintain an active transcription cycle. ...
... 14 This study proposed that c-MYC gets activated subsequently to promoter binding and that the activated form of c-MYC dissociates from promoters rapidly, likely by being degraded. 14 Indeed, further research may aid with its subsequent degradation by the nuclear proteasome to maintain an active transcription cycle. ...
The proto-oncogene c-MYC is a key representative of the MYC transcription factor network regulating growth and metabolism. MML-1 (Myc- and Mondo-like) is its homolog in C. elegans . The functional and molecular cooperation between c-MYC and H3 lysine 79 methyltransferase DOT1L was demonstrated in several human cancer types, and we have earlier discovered the connection between C. elegans MML-1 and DOT-1.1. Here, we demonstrate the critical role of DOT1L/DOT-1.1 in regulating c-MYC/MML-1 target genes genome-wide by ensuring the removal of “spent” transcription factors from chromatin by the nuclear proteasome. Moreover, we uncover a previously unrecognized proteolytic activity of DOT1L, which may facilitate c-MYC turnover. This new mechanism of c-MYC regulation by DOT1L may lead to the development of new approaches for cancer treatment.
... Abnormal MYC levels push cells to enter S-phase and undergo immortal cell division, without the need for growth factor stimulation [206]. Schuhmacher et al. provided evidence of a steady increase in cell proliferation rate in a model with increased MYC levels [207,208]. Further, Wang and colleagues demonstrated that depletion or silencing of MYC in 23 cell lines, including healthy and tumor cells, using MYC antisense oligonucleotides, led to cessation of G0/G1 or G2/M cell cycle transitions [209]. The MXD protein can prevent cell cycle progression by antagonizing MYC-mediated target gene transcription [62]; MXD shares a similar DNA binding domain with MYC and competes with MYC to bind with MAX [210]. ...
Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC. Animal testing and clinical trials have shown that sustained tumor volume reduction can be achieved when MYC is inactivated, and different combinations of therapeutic agents including MYC inhibitors are currently being developed. In this review, we first provide a summary of the multiple biological functions of the MYC oncoprotein in cancer treatment, highlighting that the equilibrium points of the MYC/MAX, MIZ1/MYC/MAX, and MAD (MNT)/MAX complexes have further potential in cancer treatment that could be used to restrain MYC oncogene expression and its functions in tumorigenesis. We also discuss the multifunctional capacity of MYC in various cellular cancer processes, including its influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, and intestinal flora. Moreover, we summarize the MYC therapy patent landscape and emphasize the potential of MYC as a druggable target, using herbal medicine modulators. Finally, we describe pending challenges and future perspectives in biomedical research, involving the development of therapeutic approaches to modulate MYC or its targeted genes. Patients with cancers driven by MYC signaling may benefit from therapies targeting these pathways, which could delay cancerous growth and recover antitumor immune responses.
... Schuhmacher et al. studied the effects of finetuned MYC protein on proliferation rate and cell cycle distribution in human lymphoblastoid p493-6 cell line. They observed that the steady increase in the fraction of cells in the S-and G2/M-phase, increased proliferation rate, and cell size relies on high levels of MYC in a dose-dependent manner, [86,87]. Using MYC antisense oligonucleotides in human lymphoid and myeloid cells prevents entry into S-phase [88,89]. ...
MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.
... Further, we recently published high expressions of genes involved in ribosomal biosynthesis in different CSC-like populations, including the here-presented BKZ-7, BKZ-8, and BKZ-9 (there referred to as LCSC_a, LCSC_b, and LCSC_c [62]). Here, we focused on known MYC target genes, such as RPLP1, RPL5, RPL14, RPL28, and LDHA [63][64][65][66][67]. Quantification revealed significant reductions in CCND1 mRNA levels for the representative LCSC-like cell populations BKZ-6 and BKZ-8 after KJ-Pyr-9 application, possibly explaining the survival-decreasing effects. ...
There is growing evidence that cancer stem cells (CSCs), a small subpopulation of self-renewal cancer cells, are responsible for tumor growth, treatment resistance, and cancer relapse and are thus of enormous clinical interest. Here, we aimed to isolate new CSC-like cells derived from human primary non-small cell lung cancer (NSCLC) specimens and to analyze the influence of different inhibitors of NF-κB and MYC signaling on cell survival. CSC-like cells were established from three squamous cell carcinomas (SCC) and three adenocarcinomas (AC) of the lung and were shown to express common CSC markers such as Prominin-1, CD44-antigen, and Nestin. Further, cells gave rise to spherical cancer organoids. Inhibition of MYC and NF-κB signaling using KJ-Pyr-9, dexamethasone, and pyrrolidinedithiocarbamate resulted in significant reductions in cell survival for SCC- and AC-derived cells. However, inhibition of the protein–protein interaction of MYC/NMYC proto-oncogenes with Myc-associated factor X (MAX) using KJ-Pyr-9 revealed the most promising survival-decreasing effects. Next to the establishment of six novel in vitro models for studying NSCLC-derived CSC-like populations, the presented investigations might provide new insights into potential novel therapies targeting NF-κB/MYC to improve clinical outcomes in NSCLC patients. Nevertheless, the full picture of downstream signaling still remains elusive.
... When Wnt pathway was activated, β-Catenin accumulated abnormally, and the expression of c-myc and cyclin D1 protein also increased correspondingly [50,51]. As a kind of oncogene, high expression of c-myc can cause abnormal cell proliferation [52], which can be used as a marker for the diagnosis of some tumors [53]. Furthermore, Cyclin D1 is an important proto-oncogene, which is often abnormally expressed in tumor tissues, such as breast cancer [54], colon cancer [55] and liver cancer [56]. ...
MiR-200a acts as a key role in tumor malignant progression. This work purposed to assess the function of miR-200a in Wilm’s tumor. Based on bioinformatics analysis, the expression, prognostic value and related pathways of miR-200a and CDC7 (a potential downstream molecule of miR-200a) in Wilm’s tumor were analyzed. qRT-PCR was conducted to confirm the miR-200a level in Wilm’s tumor cells. The luciferase reporter assay was carried out to verify the binding of miR-200a to 3′-UTR of CDC7. Then, the impacts of miR-200a and CDC7 on cell viability and apoptosis were measured using CCK-8 and flow cytometry assays. Also, western blot was applied to measure the expression of CDC7 as well as Wnt/β-catenin signaling pathway-related proteins and apoptosis proteins. Herein, we revealed that miR-200a was lowly expressed in Wilm’s tumor tissues and cells and the low miR-200a expression is closely bound up with death and poor outcomes. Moreover, miR-200a directly targeted and inhibited CDC7 in Wilm’s tumor cells. Biological function experiments illustrated that overexpression of miR-200a reduced the viability and elevated the apoptosis of Wilm’s tumor cells, while overexpression of CDC7 reversed the inhibitory impact of miR-200a on cell viability and the promoting impact of miR-200a on cell apoptosis. Besides, we revealed that miR-200a/CDC7 axis can decrease the expression of β-Catenin, Cyclin D1 and C-Myc as well as the phosphorylation of GSK-3β, thus inhibiting the Wnt/β-catenin signaling pathway. Furthermore, blocking the Wnt/β-catenin signaling pathway caused an increase on cell apoptosis, while overexpression of CDC7 can reverse these impacts. Collectively, miR-200a/CDC7 axis involved in regulating the malignant phenotype of Wilm’s tumor through Wnt/β-catenin signaling pathway, which provides a theoretical basis for targeted molecular therapy of Wilm’s tumor.
... Wnt3a, as the most common Wnt ligand, binds to the LRP5/6 receptor on the cell membrane through autocrine or paracrine forms, leading to more b-catenin accumulating in the cytoplasm of the cell that is then transferred to the nucleus [34]. Combined with specific target factors in the nucleus, specific activation of the downstream target gene c-Myc affects cell proliferation and differentiation [35]. CyclinD1 is a cyclin protein that allows cells to quickly pass through the cell cycle, thereby accelerating cell proliferation [36]. ...
Bone marrow mesenchymal stem cells (BMSCs) are thought to have great potential in the treatment of many diseases and may serve as a cell source for tissue engineering. These cells may be regulated by stromal cell-derived factor-1α (SDF-1α), which has been shown to promote the migration, proliferation, and osteogenic differentiation of BMSCs in inflammation-associated diseases. However, the specific mechanism underlying this process remains unclear. We herein transduced lentivirus carrying SDF-1α, empty vector, or siRNA-SDF-1α into mouse BMSCs and then performed transwell, CCK-8, cell cycle, alkaline phosphatase activity, and Alizarin Red staining experiments on the three groups of samples. Overexpression of SDF-1α promoted the migration, proliferation, and osteogenic differentiation of BMSCs, and SDF-1α upregulated the expression of Wnt pathway-related factors and downstream target genes as determined by western blot, real-time polymerase chain reaction, and immunofluorescence. The effect of low SDF-1α expression on BMSCs was significantly weakened. In addition, we transduced lentivirus carrying siRNA-Wnt3a into BMSCs and treated them with SDF-1 drugs. After inhibiting the Wnt pathway, SDF-1 significantly weakened the migration, proliferation, and osteogenic differentiation of BMSCs. From this, we concluded that high SDF-1 expression can promote the migration, proliferation, and osteogenic differentiation of BMSCs, at least in part by activating the Wnt pathway.
... Given that STAT6 is a transcription factor, chromatin immunoprecipitation sequencing (ChIPseq) was used to assess whether STAT6 directly binds to the promoter/enhancer regions of the aforementioned genes. ChIP-seq showed that STAT6 bound directly to the enhancer region of these targets ( (19,20), the finding that IL4 could elevate Myc expression in PDAC cells reinforces the hypothesis of a tumor-promoting role for IL4. ...
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ–IL4rα and IL2rγ–IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ–IL4rα and IL2rγ–IL13rα1 receptors signal primarily via JAK1–STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC.
Significance: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell–intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.
... Specifically, the TE was up-regulated in the high-MYC state for 882 mRNAs (TE up) and decreased (TE down) for 315 mRNAs ( Fig. 1 b and Fig. S1 l, marked in red and blue, respectively). MYC affected the total cellular mass (Schuhmacher and Eick, 2013); however, at the 24-h time point, we did not observe changes in total protein, RNA content, or cell size in P493 cells (Fig. S1,. ...
The oncogenic c-MYC (MYC) transcription factor has broad effects on gene expression and cell behavior. We show that MYC alters the efficiency and quality of mRNA translation into functional proteins. Specifically, MYC drives the translation of most protein components of the electron transport chain in lymphoma cells, and many of these effects are independent from proliferation. Specific interactions of MYC-sensitive RNA-binding proteins (e.g., SRSF1/RBM42) with 5'UTR sequence motifs mediate many of these changes. Moreover, we observe a striking shift in translation initiation site usage. For example, in low- MYC conditions, lymphoma cells initiate translation of the CD19 mRNA from a site in exon 5. This results in the truncation of all extracellular CD19 domains and facilitates escape from CD19-directed CAR-T cell therapy. Together, our findings reveal MYC effects on the translation of key metabolic enzymes and immune receptors in lymphoma cells.
... Subsequent work by other researchers also explored the role of c-Myc in cancer cells. In 2013 the present author reported that c-Myc can induce and amplify the transcription of some 447 previously reported target genes in a dosedependent manner (Schuhmacher and Eick, 2013), and in 2014 two independent groups reported that c-Myc can repress active genes and, moreover, that the amplification effect it exerts on all genes is the result of it up-regulating a specific set of target genes (Sabò et al., 2014;Walz et al., 2014; see also Dang, 2014). Older work had also shown that the genes for ribosomal RNA were probably the most important targets of c-Myc, and that the resulting increase in ribosomal RNA led to an significant increase in the total number of RNA transcripts per cell (Arabi et al., 2005;Grandori et al., 2005). ...
The transcription factor c-Myc amplifies the transcription of many growth-related genes in cancer cells, but its role as an oncogene is not fully understood.
