Promoters heterodimeric

The phosphorylated Stat proteins form homodimeric or heterodimeric complexes and are transported as such into the nucleus (Fig. 11.7). In the nucleus, they bind to corresponding DNA elements in the promoter region of cytokine responsive genes. Stimulation of transcription takes place in cooperation with other proteins such as p300, CBP (see 1.4.6), glucocorticoid receptors and c-jim. 

In contrast to the steroid receptor family, members of the thyroid receptor family typically do not associate with accessory proteins and are not localized to the extranucleus matrix. Rather, these receptors exist in the basal state associated with chromatin in the cell nucleus. When bound by hormone ligand, thyroid receptor family members dissociate from the chromatin and typically form heterodimeric combinations with the retinoid-X receptor (RXR). RXR also is capable of homodimerization in association with its ligand 9-cis retinoic acid. Thus high 9-cis retinoic acid levels apparently promote homodimerization, and low levels are permissive of heterodimerization of RXR with activation by the partner ligand. 

Of these active metabolites, endoxifen is suggested to be the primary active metabolite responsible for the majority of tamoxifen clinical efficacy, as endoxifen plasma concentrations are about five to tenfold higher than those of 4-hydroxy-tamoxifen [11, 165], Endoxifen may have additional mechanisms of action than 4-hydroxy-tamoxifen by targeting Era for degradation by proteasome [166] and through the promotion of ERa/ERf) heterodimerization, blocking ERa transcriptional activity [167],... 

A third mode of entry of Ca2+ into the cells is mediated by the coupling of the receptor to G proteins. It is believed that this is the pathway used by chemokines. The On reaction begins when the agonist induces a conformational change in the receptor which is transmitted to the G protein. The heterodimeric G protein dissociates into Ga and G 3y subunits, both of which can activate different phospholipase C (PLC) isozymes. This enzyme is able to catalyze the hydrolysis of the lipid precursor phosphatidylinositol 4,5-bisphosphate to give both 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The latter then binds to the IP3 receptor which mobilizes both stored Ca2+ and promotes an influx of external Ca2+. 

The members of the cytosolic hormone receptor family are homologous proteins and the mechanism of action involves translocation of the receptor with hormone bound to the nucleus, where it homodimerizes (or heterodimerizes with related activated receptors) and binds to specific promoters to switch on transcription of particular genes. The ultimate response to the hormonal stimulus is expression of particular proteins that variously influence development and metabolism as briefly outlined below. 

SMADs are cytoplasmic proteins with molecular weights ranging firom 42 to 60 kDa. Pathw -restricted SMADs and common or Co-SMADs are distinguished. The pathway-restricted, or receptor-regulated SMADs (R-SMADs), are phosphorylated on serines in the MH2 domain by TGF-P receptor I. The phosphorylated, receptor-regulated SMADs associate with a constitutive, common Co-SMAD (SMAD 4), and the heterodimeric SMAD comploc is translocated to the nucleus where it binds either directly or with the help of other transcriptional factors to enhancers and promoters of specific gene elements (Fig. 6.4) (see also Chapter 9). 

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