scholarly journals Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1199 ◽  
Author(s):  
Savitha Sridharan ◽  
Alakananda Basu
Keyword(s):  
Breast Cancer ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
And Function ◽  
Cell Growth And Proliferation ◽  
High Degree ◽  
Mtor Complex 1

The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.

scholarly journals Differential expression of eukaryotic translation initiation factor 4E-binding protein 2 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
Translation Initiation ◽  
Normal Breast ◽  
Translation Initiation Factor ◽  
Differentially Expressed ◽  
Initiation Factor ◽  
Primary Tumors ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding eukaryotic translation initiation factor 4E-binding protein 2, EIF4EBP2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. EIF4EBP2 was also differentially expressed in lymph node metastasis in human breast cancer. EIF4EBP2 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of EIF4EBP2 in primary tumors of the breast was correlated with recurrence-free survival in patients with luminal B and HER2+ subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. EIF4EBP2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Regulation of eIF2α Phosphorylation by MAPKs Influences Polysome Stability and Protein Translation

2021 ◽  
Author(s):  
Sana Parveen ◽  
Haripriya Parthasarathy ◽  
Dhiviya Vedagiri ◽  
Divya Gupta ◽  
Hitha Gopalan Nair ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Translation Regulation ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
Mitogen Activated Protein ◽  
Eukaryotic Translation Initiation ◽  
Polysome Stability

Regulation of protein translation occurs primarily at the level of initiation and is mediated by multiple signaling pathways, majorly mechanistic target of rapamycin complex 1 (mTORC1), mitogen-activated protein kinases (MAPKs), and the eukaryotic translation initiation factor eIF2. While mTORC1 and eIF2α influence the polysome stability, MAPKs influence the phosphorylation of the cap-binding protein eIF4E and are known to influence translation of only a small set of mRNAs. Here, we demonstrate that p38 MAPK and ERK1/2 regulate translation through integrated stress response (ISR) pathways. Dual inhibition (dual-Mi) of p38 MAPK and ERK1/2 caused substantial phosphorylation of eIF2α in a synergistic manner, resulting in near-absolute collapse of polysomes. This regulation was independent of Mnk1/2, a well-studied mediator of translation regulation by the MAPKs. Dual-Mi-induced polysome dissociation was far more striking than that caused by sodium arsenite, a strong inducer of ISR. Interestingly, induction of ISR caused increased p38 phosphorylation, and its inhibition resulted in stronger polysome dissociation, indicating the importance of p38 in the translation activities. Thus, our studies demonstrate a major, unidentified role for ERK1/2 and more particularly p38 MAPK in the maintenance of homeostasis of polysome association and translation activities.

The role of Eif2s3y in mouse spermatogenesis

2021 ◽  
Vol 16 ◽  
Author(s):  
Wenqing Liu ◽  
Na Li ◽  
Mengfei Zhang ◽  
Ahmed H. Arisha ◽  
Jinlian Hua
Keyword(s):  
Translation Initiation ◽  
Mrna Translation ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Gene Encoding ◽  
Eukaryotic Translation ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation

: Eukaryotic translation initiation factor 2 subunit 3 and structural gene Y-linked (Eif2s3y) gene, the gene encoding eIF2γ protein, is located on the mouse Y chromosome short arm. The Eif2s3y gene is globally expressed in all tissues and plays an important role in regulating global and gene-specific mRNA translation initiation. During the process of protein translation initiation, Eif2s3x(its homolog) and Eif2s3y encoded eIF2γ perform similar functions. However, it has been noticed that Eif2s3y plays a crucial role in spermatogenesis, including spermatogonia mitosis, meiosis, and spermiogenesis of spermatids, which may account for infertility. In the period of spermatogenesis, the role of Eif2s3x and Eif2s3y are not equivalent. Importance of Eif2s3y has been observed in ESC and implicated in several aspects, including the pluripotency state and the proliferation rate. Here, we discuss the functional significance of Eif2s3y in mouse spermatogenesis and self-renewal of ESCs.

scholarly journals N1-Guanyl-1,7-Diaminoheptane Sensitizes Estrogen Receptor Negative Breast Cancer Cells to Doxorubicin by Preventing Epithelial-Mesenchymal Transition through Inhibition of Eukaryotic Translation Initiation Factor 5A2 Activation

2015 ◽  
Vol 36 (6) ◽  
pp. 2494-2503 ◽  
Author(s):  
Yu Liu ◽  
Rongrong Liu ◽  
Peifen Fu ◽  
Feiya Du ◽  
Yun Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Translation Initiation ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mesenchymal Transition ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

Background: Approximately 30% of breast cancer does not express the estrogen receptor (ER), which is necessary for endocrine-based therapy approaches. Many studies demonstrated that eukaryotic translation initiation factor 5A2 (eIF5A2) serves as a proliferation-related oncogene in tumorigenic processes. Methods: The present study used cell viability assays, EdU incorporation assays, western blot, and immunofluorescence to explore whether N1-guanyl-1,7-diaminoheptane (GC7), which inhibits eIF5A2 activation, exerts synergistic cytotoxicity with doxorubicin in breast cancer. Results: We found that GC7 enhanced doxorubicin cytotoxicity in ER-negative HCC1937 cells but had little effect in ER-positive MCF-7 and Bcap-37 cells. Administration of GC7 reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in ER-negative breast cancer cells. Knockdown of eIF5A2 by siRNA inhibited the doxorubicin-induced EMT in ER-negative HCC1937 cells. Conclusion: These data demonstrated that GC7 combination therapy may enhance the therapeutic efficacy of doxorubicin in estrogen negative breast cancer cells by preventing EMT through inhibition of eIF5A2 activation.

scholarly journals Differential expression of the eukaryotic translation initiation factor EIF1B in the brain metastases of patients with breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Differential Expression ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
The Brain

Metastasis to the brain is a complication of breast cancer (1, 2) with limited treatment options (3). We mined published microarray data (4, 5) to discover genes associated with brain metastases in patients with metastatic breast cancer. We identified significant differential expression of the eukaryotic translation initiation factor EIF1B in the brain metastases of patients with breast cancer as compared to primary tumors of the breast. EIF1B may be relevant to the underlying biology by which tumor cells of the breast spread to the brain.

scholarly journals The 4E-BP growth pathway regulates the effect of ambient temperature onDrosophilametabolism and lifespan

2017 ◽  
Vol 114 (36) ◽  
pp. 9737-9742 ◽  
Author(s):  
Gil B. Carvalho ◽  
Ilaria Drago ◽  
Sany Hoxha ◽  
Ryuichi Yamada ◽  
Olena Mahneva ◽  
...  
Keyword(s):  
Ambient Temperature ◽  
Mitochondrial Protein ◽  
Model Organism ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Metabolic Switch ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Underlying Mechanisms

Changes in body temperature can profoundly affect survival. The dramatic longevity-enhancing effect of cold has long been known in organisms ranging from invertebrates to mammals, yet the underlying mechanisms have only recently begun to be uncovered. In the nematodeCaenorhabditis elegans, this process is regulated by a thermosensitive membrane TRP channel and the DAF-16/FOXO transcription factor, but in more complex organisms the underpinnings of cold-induced longevity remain largely mysterious. We report that, inDrosophila melanogaster, variation in ambient temperature triggers metabolic changes in protein translation, mitochondrial protein synthesis, and posttranslational regulation of the translation repressor, 4E-BP (eukaryotic translation initiation factor 4E-binding protein). We show that 4E-BP determinesDrosophilalifespan in the context of temperature changes, revealing a genetic mechanism for cold-induced longevity in this model organism. Our results suggest that the 4E-BP pathway, chiefly thought of as a nutrient sensor, may represent a master metabolic switch responding to diverse environmental factors.

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