Video Experimental Relacionado

Updated: Jul 10, 2025

Rapid Synthesis and Screening of Chemically Activated Transcription Factors with GFP-based Reporters

Rapid Synthesis and Screening of Chemically Activated Transcription Factors with GFP-based Reporters

Published on: November 26, 2013

Pequeñas moléculas bifuncionales que inducen la localización nuclear y la regulación transcripcional dirigida

William J Gibson^1,2, Ananthan Sadagopan^1,2, Veronika M Shoba¹

¹Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Journal of the American Chemical Society

|November 22, 2023

Resumen

Los investigadores diseñaron moléculas bifuncionales para controlar la localización de proteínas dentro de las células, lo que permite la importación nuclear dirigida para posibles terapias contra el cáncer y las enfermedades neurodegenerativas.

Área de la Ciencia:

Biología celular
La medicina molecular
Biología Química

Sus antecedentes:

La localización aberrante de proteínas está implicada en enfermedades como el cáncer y la neurodegeneración.
El objetivo de la localización de proteínas ofrece un potencial terapéutico, pero requiere mecanismos de control precisos.

Objetivo del estudio:

Diseñar moléculas bifuncionales para el control preciso de la localización subcelular de proteínas.
Investigar el potencial terapéutico de la localización inducida de proteínas para el tratamiento de enfermedades.

Principales métodos:

Desarrollo de compuestos bifuncionales que se unen a proteínas en compartimentos celulares distintos.
Utilizando BRD4 localizado en el núcleo como portador para la importación conjunta y el atrapamiento nuclear de proteínas citosólicas.
Medición de las constantes cinéticas para la difusión de los poros nucleares y evaluación de la heterogeneidad de una sola célula.

Principales resultados:

Se ha demostrado la inducción exitosa de la importación nuclear de proteínas citosólicas utilizando el sistema de ingeniería.
Cinética de difusión pasiva cuantificada a través del poro nuclear y heterogeneidad celular observada.
Mostró aplicaciones potenciales mediante la inducción de la importación nuclear de mutantes relacionados con el cáncer (NPM1c, PIK3CA^E545K) y la recableación de la expresión génica a través de la interacción BRD4-IRF1.

Conclusiones:

Las moléculas bifuncionales diseñadas controlan efectivamente la localización de proteínas, lo que permite la manipulación terapéutica.
La localización inducida de proteínas puede volver a conectar los circuitos celulares, ofreciendo nuevas estrategias terapéuticas para diversas enfermedades.

Más Videos Relacionados

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers

Published on: September 20, 2018

Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC Crosslinking of Small Molecules to Isolate Chromatin

Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC Crosslinking of Small Molecules to Isolate Chromatin

Published on: January 20, 2016

Videos de Conceptos Relacionados

Transducer Mechanism: Nuclear Receptors

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:

Regulation of Nuclear Protein Sorting

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...

Signal Transduction: Overview

Signal Transduction: Overview

Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
Typically, signal transduction involves three...

Co-activators and Co-repressors

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...

Eukaryotic Transcription Inhibitors

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...

Master Transcription Regulators

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...