El supresor tumoral Par-4 activa una vía extrínseca para la apoptosis
Ravshan Burikhanov1, Yanming Zhao, Anindya Goswami
1Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.
Cell
|July 28, 2009
Resumen
La respuesta 4 de la apoptosis prostática (Par-4) es secretada por las células e induce la apoptosis de las células cancerosas al unirse a la superficie celular GRP78.8. Esta señalización Par-4 extracelular activa una vía de muerte, ofreciendo un potencial objetivo terapéutico.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- La respuesta 4 de la apoptosis prostática (Par-4) es una proteína proapoptótica intracelular conocida.
- Par-4 se encuentra inesperadamente secretado tanto por células normales como por células cancerosas.
- La resistencia tumoral en ratones transgénicos Par-4 sugiere un papel para el Par-4 secretado.
Objetivo del estudio:
- Para investigar el mecanismo y la función de la secreción extracelular de Par-4.
- Para identificar el receptor y la vía a través de la cual la Par-4 extracelular induce la apoptosis.
- Para explorar el papel de la Par-4 extracelular en la apoptosis inducida por TRAIL.
Principales métodos:
- Cultivo celular y tratamiento con agentes inductores de estrés ER.
- Análisis de las vías de secreción de Par-4 (sensibilidad Brefeldin A).
- Investigando la interacción extracelular Par-4 con las proteínas de la superficie celular (GRP78) y la señalización aguas abajo (vía FADD/caspase).
Principales resultados:
- La Par-4 es secretada espontáneamente por las células y su secreción se ve reforzada por el estrés ER a través de una vía sensible a la brefeldina A.
- El Par-4 extracelular induce la apoptosis en las células cancerosas al unirse a la superficie celular GRP78.8.
- Esta interacción desencadena el estrés ER y activa la vía apoptótica FADD/caspasa-8/caspasa-3.
- La apoptosis inducida por TRAIL depende de la señalización extracelular Par-4 a través de la superficie celular GRP78.
Conclusiones:
- El Par-4 extracelular actúa como una molécula de señalización para inducir la apoptosis específica de las células cancerosas.
- La interacción Par-4/superficie celular GRP78 representa una nueva vía apoptótica extrínseca.
- Esta vía ofrece una potencial estrategia terapéutica para el tratamiento del cáncer.
Videos de Conceptos Relacionados
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:17The 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...
01:31The 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...