scholarly journals Relaxed initiation pausing of ribosomes drives oncogenic translation

2021 ◽  
Vol 7 (8) ◽  
pp. eabd6927
Author(s):  
Leiming Dong ◽  
Yuanhui Mao ◽  
Aidong Zhou ◽  
Xiao-Min Liu ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Translational Control ◽  
Messenger Rna ◽  
Start Codon ◽  
Ras Signaling ◽  
Oncogenic Signaling ◽  
Oncogenic Ras ◽  
Initiation Stage ◽  
Oncogenic Signaling Pathways ◽  
Quantitative Profiling

Translation is a crucial process in cancer development and progression. Many oncogenic signaling pathways target the translation initiation stage to satisfy the increased anabolic demands of cancer cells. Using quantitative profiling of initiating ribosomes, we found that ribosomal pausing at the start codon serves as a “brake” to restrain the translational output. In response to oncogenic RAS signaling, the initiation pausing relaxes and contributes to the increased translational flux. Intriguingly, messenger RNA (mRNA) m6A modification in the vicinity of start codons influences the behavior of initiating ribosomes. Under oncogenic RAS signaling, the reduced mRNA methylation leads to relaxed initiation pausing, thereby promoting malignant transformation and tumor growth. Restored initiation pausing by inhibiting m6A demethylases suppresses RAS-mediated oncogenic translation and subsequent tumorigenesis. Our findings unveil a paradigm of translational control that is co-opted by RAS mutant cancer cells to drive malignant phenotypes.

scholarly journals A Blood Pact: the Significance and Implications of eIF4E on Lymphocytic Leukemia

2018 ◽  
pp. 363-382
Author(s):  
V. VENTURI ◽  
T. MASEK ◽  
M. POSPISEK
Keyword(s):  
Translational Control ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Initiation Factor ◽  
Oncogenic Signaling ◽  
Translation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Biological Circuits ◽  
Oncogenic Signaling Pathways

Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of hematological diseases. As a node of convergence for several oncogenic signaling pathways, eIF4E has attracted a great deal of interest from biologists and clinicians whose efforts have been targeting this translation factor and its biological circuits in the battle against leukemia. The role of eIF4E in myeloid leukemia has been ascertained and drugs targeting its functions have found their place in clinical trials. Little is known, however, about the pertinence of eIF4E to the biology of lymphocytic leukemia and a paucity of literature is available in this regard that prospectively evaluates the topic to guide practice in hematological cancer. A comprehensive analysis on the significance of eIF4E translation factor in the clinical picture of leukemia arises, therefore, as a compelling need. This review presents aspects of eIF4E involvement in the realm of the lymphoblastic leukemia status; translational control of immunological function via eIF4E and the state-of-the-art in drugs will also be outlined.

scholarly journals MZF1 and SCAND1 Reciprocally Regulate CDC37 Gene Expression in Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 792 ◽  
Author(s):  
Takanori Eguchi ◽  
Thomas L. Prince ◽  
Manh Tien Tran ◽  
Chiharu Sogawa ◽  
Benjamin J. Lang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Heat Shock Protein 90 ◽  
Prostate Cancer Cells ◽  
Oncogenic Signaling ◽  
Normal Prostate ◽  
Elevated Expression ◽  
The Stability ◽  
Oncogenic Signaling Pathways

Cell division control 37 (CDC37) increases the stability of heat shock protein 90 (HSP90) client proteins and is thus essential for numerous intracellular oncogenic signaling pathways, playing a key role in prostate oncogenesis. Notably, elevated expression of CDC37 was found in prostate cancer cells, although the regulatory mechanisms through which CDC37 expression becomes increased are unknown. Here we show both positive and negative regulation of CDC37 gene transcription by two members of the SREZBP-CTfin51-AW1-Number 18 cDNA (SCAN) transcription factor family—MZF1 and SCAND1, respectively. Consensus DNA-binding motifs for myeloid zinc finger 1 (MZF1/ZSCAN6) were abundant in the CDC37 promoter region. MZF1 became bound to these regulatory sites and trans-activated the CDC37 gene whereas MZF1 depletion decreased CDC37 transcription and reduced the tumorigenesis of prostate cancer cells. On the other hand, SCAND1, a zinc fingerless SCAN box protein that potentially inhibits MZF1, accumulated at MZF1-binding sites in the CDC37 gene, negatively regulated the CDC37 gene and inhibited tumorigenesis. SCAND1 was abundantly expressed in normal prostate cells but was reduced in prostate cancer cells, suggesting a potential tumor suppressor role of SCAND1 in prostate cancer. These findings indicate that CDC37, a crucial protein in prostate cancer progression, is regulated reciprocally by MZF1 and SCAND1.

scholarly journals Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation

2013 ◽  
Vol 42 (5) ◽  
pp. 2932-2944 ◽  
Author(s):  
Tsung-Ming Chen ◽  
Yu-Heng Shih ◽  
Joseph T. Tseng ◽  
Ming-Chih Lai ◽  
Chih-Hao Wu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Protein Synthesis ◽  
Protein Expression ◽  
Cancer Cells ◽  
Translational Control ◽  
Messenger Rna ◽  
Upstream Open Reading Frame ◽  
Colon Cancer Cells ◽  
Aberrant Expression ◽  
Translational Activation

AbstractHuman fibroblast growth factor 9 (FGF9) is a potent mitogen involved in many physiological processes. Although FGF9 messenger RNA (mRNA) is ubiquitously expressed in embryos, FGF9 protein expression is generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in human malignancies including cancers, but the mechanism remains largely unknown. Here, we report that FGF9 protein, but not mRNA, was increased in hypoxia. Two sequence elements, the upstream open reading frame (uORF) and the internal ribosome entry site (IRES), were identified in the 5' UTR of FGF9 mRNA. Functional assays indicated that FGF9 protein synthesis was normally controlled by uORF-mediated translational repression, which kept the protein at a low level, but was upregulated in response to hypoxia through a switch to IRES-dependent translational control. Our data demonstrate that FGF9 IRES functions as a cellular switch to turn FGF9 protein synthesis ‘on’ during hypoxia, a likely mechanism underlying FGF9 overexpression in cancer cells. Finally, we provide evidence to show that hypoxia-induced translational activation promotes FGF9 protein expression in colon cancer cells. Altogether, this dynamic working model may provide a new direction in anti-tumor therapies and cancer intervention.

scholarly journals Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3666
Author(s):  
Naoshi Nishida
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Immune Microenvironment ◽  
Oncogenic Signaling ◽  
Oncogenic Pathways ◽  
Tumor Immune Microenvironment ◽  
Oncogenic Signaling Pathways

The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases.

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