Related Experiment Video

Updated: Mar 3, 2026

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

eIF2α Phosphorylation Mediates IL24-Induced Apoptosis through Inhibition of Translation

Leah Persaud^1,2, Xuelin Zhong^1,2, Giselle Alvarado¹

¹Department of Biological Sciences, Herbert H. Lehman College, City University of New York, Bronx, New York.

Molecular Cancer Research : MCR

|May 3, 2017

Insights

Interleukin-24 (IL24) inhibits cancer cell growth by blocking protein translation initiation through two key pathways: eIF2α phosphorylation and 4E-BP1 dephosphorylation, ultimately inducing apoptosis.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Interleukin-24 (IL24) is an immunomodulatory cytokine with demonstrated tumor-suppressor effects, including inhibiting angiogenesis and sensitizing cancer cells to chemotherapy.
Overexpression or supra-physiologic activation of translation initiation factors is linked to cancer initiation, progression, aggressiveness, and poor prognosis.
Two critical translation initiation complexes, the ternary complex and the eIF4F complex, are regulated by the phosphorylation status of eIF2α and 4E-BP1, respectively.

Purpose of the Study:

To investigate the role of IL24 in regulating translation initiation in squamous cell carcinoma.
To determine the specific molecular mechanisms by which IL24 affects translation initiation and induces apoptosis.
To provide direct evidence for IL24's control over gene-specific expression via translation regulation.

Main Methods:

Utilized a dominant constitutively active mutant of eIF2α (eIF2α-S51A) resistant to phosphorylation to assess its involvement in IL24-induced apoptosis.
Administered IL24 treatment to cancer cells and monitored protein synthesis inhibition, downstream biomarker expression (e.g., CHOP), and apoptosis induction.
Analyzed the phosphorylation status of 4E-BP1 and its interaction with eIF4E following IL24 treatment.

Main Results:

IL24 treatment led to significant inhibition of protein synthesis and induced apoptosis in cancer cells, evidenced by CHOP expression.
The constitutively active eIF2α-S51A mutant abrogated both the IL24-mediated translational block and the induction of apoptosis.
IL24 treatment resulted in hypophosphorylation of 4E-BP1, disrupting the eIF4F complex assembly.

Conclusions:

IL24 inhibits translation initiation in squamous cell carcinoma through a novel mechanism involving both eIF2α phosphorylation and 4E-BP1 dephosphorylation.
These findings establish a previously unrecognized role for IL24 in controlling protein synthesis and inducing cancer-specific apoptosis.
This study provides the first direct evidence that IL24 regulates gene-specific expression by modulating translation initiation.

Read full analysis

Abstract:

IL24 is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor-suppressor activities of IL24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. Supra-physiologic activation and/or overexpression of translation initiation factors are implicated in the initiation and progression of cancer animal models as well as a subset of human cancers. Activation and/or overexpression of translation initiation factors correlate with aggressiveness of cancer and poor prognosis. Two rate-limiting translation initiation complexes, the ternary complex and the eIF4F complex, are regulated by eIF2α and 4E-BP1 phosphorylation, respectively. The work reported here provides direct evidence that IL24 induces inhibition of translation initiation leading to apoptosis in squamous cell carcinoma. A dominant constitutively active mutant of eIF2α, which is resistant to phosphorylation, was used to determine the involvement of eIF2α in IL24-induced apoptosis. Treatment with IL24 resulted in inhibition of protein synthesis, expression of downstream biomarkers of ternary complex depletion such as CHOP, and induction of apoptosis in cancer cells. The constitutively active nonphosphorylatable mutant of eIF2α, eIF2α-S51A, reversed both the IL24-mediated translational block and IL24-induced apoptosis. Intriguingly, IL24 treatment also caused hypophosphorylation of 4E-BP1, which binds to eIF4E with high affinity, thus preventing its association with eIF4G and therefore preventing elF4F complex assembly.Implications: These results demonstrate a previously unrecognized role of IL24 in inhibition of translation, mediated through both phosphorylation of eIF2α and dephosphorylation of 4E-BP1, and provide the first direct evidence for translation control of gene-specific expression by IL24. Mol Cancer Res; 15(8); 1117-24. ©2017 AACR.

More Related Videos

Xenopus laevis as a Model to Identify Translation Impairment

Xenopus laevis as a Model to Identify Translation Impairment

Published on: September 27, 2015

Analysis of Translation Initiation During Stress Conditions by Polysome Profiling

Analysis of Translation Initiation During Stress Conditions by Polysome Profiling

Published on: May 19, 2014

Related Concept Videos

Regulation of the Unfolded Protein Response

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...

The Intrinsic Apoptotic Pathway

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...

Initiation of Translation

Initiation of Translation

Initiating translation is complex because it involves multiple molecules. Initiator tRNA, ribosomal subunits, and eukaryotic initiation factors (eIFs) are all required to assemble on the initiation codon of mRNA. This process consists of several steps that are mediated by different eIFs.
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...

The Extrinsic Apoptotic Pathway

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...

Leaky Scanning

Leaky Scanning

During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...

The Unfolded Protein Response

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...

Articles linked to this work by shared authors, journal, and citation graph.

Mechanisms and therapeutic opportunities of the ribotoxic stress response in cancer.

Molecular oncology·2026

Identification of new Trypanosoma cruzi-specific protein synthesis inhibitors by using a developed high-throughput in vitro translation assay.

International journal for parasitology. Drugs and drug resistance·2026

Vorinostat Inhibition of FOXM1 Oncogenic Signaling Is Associated With the Downregulation of MYCN Transcription in Metastatic Retinoblastoma.

Journal of biochemical and molecular toxicology·2026

Inhibitory Effect of Interleukin-24 on Programmed Death Ligand 1 Expression via a Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2-Dependent Pathway in Human Triple-Negative Breast Cancer.

Genes·2026

Objective Assessment of Physical Activity in Breast Cancer Survivors: Associations With Adiposity and Metabolic Parameters of Glucose and Insulin-Insights From NHANES.

Cancer reports (Hoboken, N.J.)·2025

Interleukin 24 Promotes Mitochondrial Dysfunction, Glucose Regulation, and Apoptosis by Inactivating Glycogen Synthase Kinase 3 Beta in Human Prostate Cancer Cells.

Cells·2025

See all related articles