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Coactivadores y Corepresores

Doctorado en Biociencias

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ProtenasActivadoras

Acetiltransferasa

Estimula yestabiliza

Velocidad de la

transcripcin

CoactivadoresProteicos

Secuenciasconcenso

Mediator

Competencia

Represores

Evita contactoActivador- Maquinaria

Interferencia directa

Con el ensamblajeDel aparato T.

Aparato deTranscripcin

basal

Cromatinanica combinacin

De protenas

Bloquea iniciacin

DisminuyeVelocidad

indirecta directa

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ReceptoresNucleares

F. TranscripcinLigando-Regulados

TransduccinHormonal de seales

(H. Steroids )Coactivadores

Afecta maquinaria

De Transcripcin

ActividadEnzimtica

Histone AcetiltransferasaMethyltransferasaUbiquitin ligases

Influencian puntosClaves en

Transcripcin

Agentes deCarcinogenesis

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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.

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Heterogeneous structure and funcion

Enhance NR mediated transcriptioPrimarly by binding to the ligand-activated

Receptor. (one or mor NR boxes)Coactivator interaction can also occur with

The N-Terminal activation function-1 ofThe receptor.

Unlike Nrs which adhere to a common

Structural theme, coactivators are diverseIn both structure and functions:

However, for many coactivators, a sharedCharacteristic is their enzymatic activities

That promote transcription:- SRC family, CBP and p300

How the enzymatic activities of these UPPContribute to transcription is unclear

at this point

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Spatial and temporal

expression of coactivatorsThe 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

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Coactivator interaction with the promoter is acoordinated, orderly process

It has been revealed that transcription initiation is an orderly prcess: coactivators withdistinct enzymatic properties are sequentially recruited and prepare the way for subsequentcoactivators that contribute to the alteration of the promoter to effect a functional RNA

polymerase II (pol II) -promoter interaction

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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 byCARM1

Orderly coactivator recruitment is essential for efficient

transcription to ensue.

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Coactivators in cancerCoactivators Important role in Hormone

Dependent Cancer.

Growth-factorKinase pathways

SRC-3 and othercoactivators

Target ofphospphorylation

Commonly hyperactivatedIn cancerous cell

Coactivator overexpressionAnd kinase hyperactivation

Concerted mechanism thatContributes to

Cell growth and carcinogenesis

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Other diseasesCoactivator mis-expression is involved in other pathological conditions.

Germline mutations affecting CBPresults 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 andmotor defects. (Matsuura, T. et al. 1997)

Single nucleotide polymorphisms inPGC-1 have been associated with increased susceptibilityto type II diabetes. (Ek, J. Et al. 2001. Hara, K. Et al. 2002)

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Gracias.