Other approaches for selective actions

Modifications of the AR such as splice variants, isoforms or postranslational modifications may effect the interaction of the androgen with the receptor and determine tissue selectivity, but not much is known yet. Recent publications (Kousteni et al. 2001; Migliaccio et al. 2000) stress the importance of transcription-independent, nongenomic actions of steroids, reflecting the observation of rapid effects, mediated by hormones and their hormone receptors within minutes, thereby excluding transcription-dependent activity (genomic action). It was demonstrated that kinases such as PI3K/AKT (Castoria et al. 2003) on one side or Src/Ras/MEK (Kousteni et al. 2003) on the other side are downstream targets of the activated receptors. It is very likely that the necessary interaction with proteins for nonge-nomic action also depends on the ability of the ligand bound hormone receptor to adopt specific conformations which may differ from the conformation necessary for DNA-binding and transactivation. However this is highly speculative and it is unknown at this time if a preferential transcription-independent action could

whole brain

cerebellum, left

substantia nigra

heart

esophagus

colon, transverse

kidney

lung

liver

leukemia, HL-60

fetal i

yeast total RNA

cerebral cortex

cerebellum, right

accumbens nucleus

aorta

stomach

colon, desending

skeletal muscle

placenta

pancreas

He La S3

letal heart

yeasi tRNA

fro nial lobe

corpus callosum

thalamus

atrium, left

duodenum

rectum

spleen

bladder

adrenal gland

leukemia, K-562

lata! kîdney

E. coli rRNA

parietal lobe

amygdala

pituitary gland

atrium, right

jejunum

thymus

uterus

thyroid gland

leukemia, MOLT-4

letal liver

£ coli DNA

occipital lobe

caudate nucleus

it

ventricle, left

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peripheral blood leukocyte

prostate

salivary gland

Burkitt's lymphoma, Raji

fetal spleen

Poly rlA)

temporal lobe

hippocampus

ventricle, right

ilocecum

lymph node

testis

mammary gland

Burkitt's lymphoma, Daudi

letal thymus

human Cgl-I DNA

p. g.- of cerebral cortex

medulla oblongata

interventricular septum

appendix

bone morrow

ovary

colorectal adenocarcinoma, SW480

fetal lung

X

putamen

apex of the heart

colon, ascending

trachea

lung carcinoma, A549

human DNA 500 ng

* paracentral gyrus

The expression of the AR-specific coactivator FHL2 is restricted to distinct tissue FHL2 is expressed in the heart only (arrows). PolyA+ RNAs from human tissues and cell lines were prepared, transferred onto a membrane and probed with the labelled cDNA for FHL2 followed by autoradiography. Major expression (arrows) of FHL2 was in the fetal (B11) and adult (A4) heart, left and right ventricle (E4, F4), the interventricular septum (G4) and the apex (H4) of the heart.

be beneficial for hypogonadism or PCa treatment. Effects which are suggested for nongenomic actions of steroid receptors includes beneficial and undesired effects on proliferation, protection of neurons and osteoblasts, and vasorelaxation (Cato etal. 2002; Sci STKE).

The identification of hormones which selectively alter genomic vs. nongenomic effects and signalling may lead to the development of novel compounds that specifically modulate the signals in vivo. First examples for androgens which were able to modulate genomic and nongenomic responses differentially were described (Lutz et al. 2003). However, it is not clear if such approaches will lead to tissue-selective hormones.

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