ArticleThe Journal of biological chemistry2015
A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 60 citations in OpenAlex.
- Early life stress-induced depression reveals distinct region-specific modulation of unfolded protein response genes in the prefrontal cortex and hippocampus of rats.Frontiers in psychiatry · 2026Article
- In Vitro Effects of Boric Acid on Cell Cycle, Apoptosis, and miRNAs in Medullary Thyroid Cancer Cells.Biological trace element research · 2025Article
- The role of cell cycle-related genes in the tumorigenesis of adrenal and thyroid neuroendocrine tumors.Heliyon · 2025Review
- An Overview of Research Advances in Oncology Regarding the Transcription Factor ATF4.Current drug targets · 2025Review
- ATF4-mediated expression of NOXA is critical for Necroptosis driven by Glucose Deprivation.Frontiers in cell death · 2025Article
- Thyroid C-Cell Biology and Oncogenic Transformation.Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer · 2025Review
- Systemic therapies for medullary thyroid carcinoma: state of the art.Therapeutic advances in endocrinology and metabolism · 2025Review
- ATF4 in cellular stress, ferroptosis, and cancer.Archives of toxicology · 2024Review
- ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor.Biology · 2024Review
- ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Oestrogen Receptor-Positive Breast Cancer.Pathobiology : journal of immunopathology, molecular and cellular biology · 2024Article
- Molecular Basis and Natural History of Medullary Thyroid Cancer: It is (Almost) All in theCancers · 2023Review
- Targeting the RET tyrosine kinase in neuroblastoma: A review and application of a novel selective drug design strategy.Biochemical pharmacology · 2023Review
- A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response.Frontiers in molecular neuroscience · 2023Review
- Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy.The Journal of nutrition · 2022Review
- Dissecting chicken germ cell dynamics by combining a germ cell tracing transgenic chicken model with single-cell RNA sequencing.Computational and structural biotechnology journal · 2022Article
- Article
- Hallmarks of RET and Co-occuring Genomic Alterations inMolecular cancer therapeutics · 2021Review
- ONC201 Shows Potent Anticancer Activity Against Medullary Thyroid Cancer via Transcriptional Inhibition ofMolecular cancer therapeutics · 2021Article
- Article
- The role of host eIF2α in viral infection.Virology journal · 2020Review
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation-dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.