Abstract
Basic Helix-loop-Helix (bHLH) factors play a significant role in both development and disease. bHLH factors function as protein dimers where two bHLH factors compose an active transcriptional complex. In various species, the bHLH factor Twist has been shown to play critical roles in diverse developmental systems such as mesoderm formation, neurogenesis, myogenesis, and neural crest cell migration and differentiation. Pathologically, Twist1 is a master regulator of epithelial-to-mesenchymal transition (EMT) and is causative of the autosomal-dominant human disease Saethre Chotzen Syndrome (SCS). Given the wide spectrum of Twist1 expression in the developing embryo and the diverse roles it plays within these forming tissues, the question of how Twist1 fills some of these specific roles has been largely unanswered. Recent work has shown that Twists biological function can be regulated by its partner choice within a given cell. Our work has identified a phosphoregulatory circuit where phosphorylation of key residues within the bHLH domain alters partner affinities for Twist1; and more recently, we show that the DNA binding affinity of the complexes that do form is affected in a cis-element dependent manner. Such perturbations are complex as they not only affect direct transcriptional programs of Twist1, but they indirectly affect the transcriptional outcomes of any bHLH factor that can dimerize with Twist1. Thus, the resulting lineage-restricted cell fate defects are a combination of loss-of-function and gain-offunction events. Relating the observed phenotypes of defective Twist function with this complex regulatory mechanism will add insight into our understanding of the critical functions of this complex transcription factor.
Keywords: Twist1, bHLH, transcription, dimerization, DNA binding, Saethre Chotzen Syndrome, limb development, phosphorylation
Current Medicinal Chemistry
Title: Phosphoregulation of Twist1 Provides a Mechanism of Cell Fate Control
Volume: 15 Issue: 25
Author(s): Anthony B. Firulli and Simon J. Conway
Affiliation:
Keywords: Twist1, bHLH, transcription, dimerization, DNA binding, Saethre Chotzen Syndrome, limb development, phosphorylation
Abstract: Basic Helix-loop-Helix (bHLH) factors play a significant role in both development and disease. bHLH factors function as protein dimers where two bHLH factors compose an active transcriptional complex. In various species, the bHLH factor Twist has been shown to play critical roles in diverse developmental systems such as mesoderm formation, neurogenesis, myogenesis, and neural crest cell migration and differentiation. Pathologically, Twist1 is a master regulator of epithelial-to-mesenchymal transition (EMT) and is causative of the autosomal-dominant human disease Saethre Chotzen Syndrome (SCS). Given the wide spectrum of Twist1 expression in the developing embryo and the diverse roles it plays within these forming tissues, the question of how Twist1 fills some of these specific roles has been largely unanswered. Recent work has shown that Twists biological function can be regulated by its partner choice within a given cell. Our work has identified a phosphoregulatory circuit where phosphorylation of key residues within the bHLH domain alters partner affinities for Twist1; and more recently, we show that the DNA binding affinity of the complexes that do form is affected in a cis-element dependent manner. Such perturbations are complex as they not only affect direct transcriptional programs of Twist1, but they indirectly affect the transcriptional outcomes of any bHLH factor that can dimerize with Twist1. Thus, the resulting lineage-restricted cell fate defects are a combination of loss-of-function and gain-offunction events. Relating the observed phenotypes of defective Twist function with this complex regulatory mechanism will add insight into our understanding of the critical functions of this complex transcription factor.
Export Options
About this article
Cite this article as:
Firulli B. Anthony and Conway J. Simon, Phosphoregulation of Twist1 Provides a Mechanism of Cell Fate Control, Current Medicinal Chemistry 2008; 15 (25) . https://dx.doi.org/10.2174/092986708785908987
DOI https://dx.doi.org/10.2174/092986708785908987 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Transcription Factors as Potential Targets for Therapeutic Drugs
Current Pharmaceutical Biotechnology Trace of Long Non-Coding RNAs in Signaling Pathways in Thyroid Cancer
Current Signal Transduction Therapy Key Epigenetic Events Involved in the Maintenance of Breast Cancer Stem Cells
Current Stem Cell Research & Therapy Realizing the Potential of Health-Promoting Rosehips from Dogroses (Rosa sect. Caninae)
Current Bioactive Compounds Cytotoxicity, Docking Study of New Fluorinated Fused Pyrimidine Scaffold: Thermal and Microwave Irradiation Synthesis
Medicinal Chemistry Pro-apoptotic Activity of BH3-only Proteins and BH3 Mimetics: from Theory to Potential Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Decreased Vascular Repair and Neovascularization with Ageing: Mechanisms and Clinical Relevance with an Emphasis on Hypoxia- Inducible Factor-1
Current Molecular Medicine Pharmaceutical Approaches for Optimizing Oral Anti-Inflammatory Delivery Systems
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry TNF-α and Ghrelin: Opposite Effects on Immune System, Metabolism and Mental Health
Protein & Peptide Letters Synthesis and Anti-thyroid Cancer Effect of Iodo-chrysin Derivatives
Medicinal Chemistry Role of p53 Gene in Breast Cancer: Focus on Mutation Spectrum and Therapeutic Strategies
Current Pharmaceutical Design The Clinical Characteristics and Survival Profiles of Wilms Tumor in the United Arab Emirates: A Single-center Retrospective Analysis
New Emirates Medical Journal Molecular Docking, Drug-Likeness and ADMET Analysis, Application of Density Functional Theory (DFT) and Molecular Dynamics (MD) Simulation to the Phytochemicals from Withania Somnifera as Potential Antagonists of Estrogen Receptor Alpha (ER- α)
Current Computer-Aided Drug Design New Strategies in the Chemotherapy of Leukemia: Eradicating Cancer Stem Cells in Chronic Myeloid Leukemia
Current Cancer Drug Targets ROCK Inhibitors as Emerging Therapeutic Candidates for Sarcomas
Current Cancer Drug Targets Physiology of Immune System: Regulation of Stem Cell Survival
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Structure Based Design, Synthesis, and Evaluation of Potential Inhibitors of Steroid Sulfatase
Current Topics in Medicinal Chemistry Inhibition of Autophagy Strengthens Celastrol-Induced Apoptosis in Human Pancreatic Cancer In Vitro and In Vivo Models
Current Molecular Medicine Evaluating Potential P-gp Substrates: Main Aspects to Choose the Adequate Permeability Model for Assessing Gastrointestinal Drug Absorption
Mini-Reviews in Medicinal Chemistry Oncogenic Signaling Pathways Activated by RON Receptor Tyrosine Kinase
Current Cancer Drug Targets