Coactivadores y Corepresores

Doctorado en Biociencias

Coactivadores Proteicos Acetiltransferasa

indirecta

Protenas Activadoras

directa

Estimula y estabiliza Aparato de Transcripcin basal

Velocidad de la transcripcin nica combinacin De protenas Secuencias concenso

Cromatina

Mediator

Competencia

Evita contacto Activador- Maquinaria Represores Interferencia directa Con el ensamblaje Del aparato T.

Disminuye Velocidad Bloquea iniciacin

Receptores Nucleares

F. Transcripcin Ligando-Regulados

Coactivadores

Transduccin Hormonal de seales (H. Steroids )

Afecta maquinaria De Transcripcin

Actividad Enzimtica

Histone Acetiltransferasa Methyltransferasa Ubiquitin ligases

Influencian puntos Claves en Transcripcin

Agentes de Carcinogenesis

Nuclear Receptor superfamily

Ligand regulated transcription factors for steroid, thyroids, retinoid hormones and other lipophilic ligands. The biology of Nrs relies on coactivators proteins that interact with Nrs And enhance their ability to activate transcription.

Heterogeneous structure and funcion

Enhance NR mediated transcriptio Primarly by binding to the ligand-activated Receptor. (one or mor NR boxes) Coactivator interaction can also occur with The N-Terminal activation function-1 of The receptor. Unlike Nrs which adhere to a common Structural theme, coactivators are diverse In both structure and functions: However, for many coactivators, a shared Characteristic is their enzymatic activities That promote transcription: - SRC family, CBP and p300 How the enzymatic activities of these UPP Contribute to transcription is unclear at this point

Spatial and temporal expression of coactivators

The expression level of SRC-1 is higher in uterine tissue compared with breast tissue, where its higher expression has been show to contribute to the selective estrogen-receptor modulator 4-hydroxy-tamoxifen, which behaves as an estrogen agonist in the uterus Selective recruitment of specific subsets of coactivators with synthetic receptor ligands Induce unique ligand-binding domain conformation Likely to represent a promising approach for drugs Manifestation of the desirable aspects of the biology of a particular NR while diminishing the undesirable parts

Coactivator interaction with the promoter is a coordinated, orderly process

It has been revealed that transcription initiation is an orderly prcess: coactivators with distinct enzymatic properties are sequentially recruited and prepare the way for subsequent coactivators that contribute to the alteration of the promoter to effect a functional RNA polymerase II (pol II) -promoter interaction

Orderly process
- in vitro, The ordered addition of SRC-1 followed by p300 resulted in optimal transcription. -Earlier studies also have shown that pre-methylation of histone H4 by PRMT1 enchances acetylation by p300. - Pre-acetylation of an H3 peptide by p300 enhances methylation by CARM1 Orderly coactivator recruitment is essential for efficient transcription to ensue.

Coactivators in cancer
Coactivators Important role in Hormone Dependent Cancer.

Growth-factor Kinase pathways

Target of phospphorylation

SRC-3 and other coactivators

Commonly hyperactivated In cancerous cell

Coactivator overexpression And kinase hyperactivation

Concerted mechanism that Contributes to Cell growth and carcinogenesis

Other diseases
Coactivator mis-expression is involved in other pathological conditions. Germline mutations affecting CBP results in RubinsteinTaybi syndrome, a disease characterized by mental retardation and facial abnormalities (Petrij, F. et al. 1995) Mutation of the gene encoding E6-AP is associated with another genetic disease, Angelman syndrome, which is characterized by profound mental retardation and motor defects. (Matsuura, T. et al. 1997) Single nucleotide polymorphisms in PGC-1 have been associated with increased susceptibility to type II diabetes. (Ek, J. Et al. 2001. Hara, K. Et al. 2002)

Gracias.