Cross references: Hormones in General Steroids
Receptors in General Receptor Evolution
Receptors Evolution Timeline Intracellular Receptors
Testosterone Receptor Testosterone Serotonin Interaction
The information on this page resulted from several different searches.
I conducted the searches from oldest to newest because I was completely unfamiliar with the subject, and I wanted to familiarize myself with the subject as it evolved.
PubMed search for "testosterone transcription factor"
The relationship between adrogen receptors and the hormonally controlled responses of rat ventral prostate. (PubMed)
This 1976 paper is the oldest full-length paper found when searching PubMed for 'testosterone transcription factor'. It was reference 4708<4751 on page 236<238.
As of 1979, the papers all discuss measurement of the quantity of testosterone receptor without any attempt to determine to which section of DNA the receptor is binding, which mRNA is being transcribed or which protein is being synthesized as a consequence of receptor binding.
Hormonal control of gene expression: differential activation of rat bone marrow RNA polymerases by erythropoietin and testosterone.
Ref 4437<4751 on page 222<238 1979
This is the first reference to have "RNA" in the title.
Analysis of regulatory sequences in androgen-responsive genes
Ref 3572<4751 on page 179<238 1988
This is the first hint that a testosterone receptor might possibly bind to more than one gene.
mRNA synthesis rates in vivo for androgen-inducible sequences in mouse kidney
Ref 3519<4751 on page 176<238 1988
"... in vivo rates of mRNA synthesis ... were measured for the androgen-inducible mRNAs coding for beta-glucuronidase (GUS), ornithine decarboxylase (ODC), the protein coded by the RP-2 gene, and the so-called kidney androgen-regulated protein (KAP)."
"Testosterone markedly increased the synthesis of the androgen-inducible mRNAs, but not the control mRNAs. Induction was not seen in mutant mice lacking functional androgen receptor protein. ... For GUS, ODC, and RP-2 mRNAs ... induction of synthesis was rapidly reversed after testosterone removal."
If testosterone was able to induce four distinct mRNAs, doesn't that imply four distinct testosterone transcription factors? This may be what I was looking for.
Gene Activity during the Early Phase of Androgen-stimulated Rat Prostate Regrowth (PubMed)
Ref 3369<4751 on page 169<238 1989
"Androgenic steroids regulate the ... changes in the expression of individual genes during the early phase of prostate regrowth. ... increased numbers of replicating cells within 12 h of continuous pharmacological testosterone replacement ... accompanied by the sequential induction of a variety of transcripts encoding gene products often associated with cell growth.
Within 1 h of treatment, mature mRNA transcripts for c-fos were induced 6-fold, returning to control levels by 2 h. Other genes showed transiently elevated transcript levels after 2 h (c-Ha-ras, c-Ki-ras) or after 8 h (c-myc,c-myb, beta-actin, and Mr 70,000 heat shock protein) of testosterone replacement.
Expression of the polypeptide encoded by c-Ha-ras was coordinately enhanced (2-fold) during this period, but not to the levels of the transcript (20-fold induction). Transcripts encoding basic fibroblast growth factor were increased 16 h and later, subsequent to the earlier enhancement in the proliferation rate."
"The complexity of the response of the prostate gland to androgens is reflected in the large number of genes the expression of which fluctuates during androgenic stimulation."
These six genes may represent six distinct testosterone transcription factors in addition to the four genes found in the preceding reference.
Progressive induction of mRNA synthesis for androgen-responsive genes in mouse kidney ( PubMed)
Ref 3336<4751 on page 167<238 1989
"A number of mRNAs present in kidney are selectively induced by the administration of androgen ... seven androgen-responsive mRNAs were tested. The time courses of induction following testosterone treatment indicated that androgen-responsive mRNA synthesis increases progressively. ... it took 2-10 days after the start of hormone administration for synthesis rates to reach a maximum."
I think this implies seven distinct testosterone transcription factors.
So far I've scanned the titles through page 167<238.
PubMed search for:
"mRNA synthesis androgen-responsive genes"
I felt that this was taking too long, so I changed the search terms to:
"mRNA synthesis androgen-responsive genes ".
This reduced the number of titles I had to wade through from 3336 still to go out of a total of 4751 to just 114 on 6 pages .
Isolation and characterisation of genes for androgen-responsive secretory proteins of rat seminal vesicles (PubMed)
Ref 113<114 on page 6<6 1983
I didn't find this paper particularly helpful. However, its 'Cited by ...' section did list one reference which was useful.
Sequence organisation of rat seminal vesicle F gene: location of transcriptional start point and sequence comparison with six other androgen-regulated genes (PubMed)
Cited by Ref 113, above. 1985.
"We compared the 5' regions of S and F genes with three rat prostate genes (Cl, C2 and C3) and two mouse renin genes (Ren 1 and Ren 2) - the only androgen-responsive genes for which sufficient sequence data are available. Unfortunately, they do not constitute seven independent genes but three evolutionarily-related groups (seminal vesicle, prostate and renin). Upstream the seminal vesicle and prostatic genes can be compared fairly easily. In contrast, Ren 1 and Ren 2 diverge approximately 180 bp upstream from the cap site, due mainly to the inclusion of an Alu-2 repetitive element in Ren 2, but at a point 200 bp further upstream strong homology is resumed"
I don't completely understand this, but I'm not uncomfortable about concluding that this implies the existence of seven distinct testosterone transcription factors. Although the Abstract for Ref 3336, above, didn't specify which genes were inducing mRNA synthesis, the PDF for Ref 3369 specified six genes and the PDF for Ref 3519 specified four genes, all of which are different from the seven genes specified in this study. That implies the existence of at least seventeen distinct testosterone transcription factors.
Identification of androgen-regulated genes in the prostate cancer cell line LNCaP by serial analysis of gene expression and proteomic analysis (PubMed)
Ref 66<114 on page 4<6 2001
"To develop a better understanding of the effect of androgen on prostatic cells, we have analyzed gene expression changes induced by dihydrotestosterone (DHT) in the androgen responsive prostate cancer line LNCaP, at both RNA and protein levels. Changes at the RNA level induced by DHT were determined by means of serial analysis of gene expression (SAGE), and protein profiling was done by means of quantitative two-dimensional polyacrylamide gel electrophoresis. ... Some 351 genes were significantly affected by DHT treatment at the RNA level (p < 0.05), of which 147 were induced and 204 repressed by androgen. In two independent experiments, the integrated intensity of 32 protein spots increased and 12 decreased at least two-fold in response to androgen, out of a total of 1031 protein spots analyzed. The change in intensity for most of the affected proteins identified could not be predicted based on the level of their corresponding RNA. Our study provides a global assessment of genes regulated by DHT and suggests a need for profiling at both RNA and protein levels for a comprehensive evaluation of patterns of gene expression."
If I understand correctly, this indicates the presence of 351 DHT transcription factors.
Scanning the titles of the remaining 65 other references located by this search revealed many other "mRNA synthesis androgen-responsive genes". Unfortunately, there was no summary article which listed all the "mRNA synthesis androgen-responsive genes". Perhaps the effort is still too young.
Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells (PubMed)
Ref 21<114 on page 3<6 2007
"... isoflavone concentrate (ISF) ... upregulated 80 genes and downregulated 33 genes (P<0.05) involving androgen-regulated genes and pathways controlling cell cycle, metabolism, and intracellular trafficking."
"Prostate-specific antigen, homeobox protein NKX3, and cyclin B mRNA were significantly reduced, whereas mRNA was significantly upregulated for p21CIP1, a major cell cycle inhibitory protein, and fatty acid and cholesterol synthesis pathway genes. ISF also significantly increased cyclin-dependent kinase inhibitor p27KIP1 and FOXO3A/FKHRL1, a forkhead transcription factor. A differential pattern of androgen-regulated genes was apparent with genes involved in prostate cancer progression being downregulated by ISF, whereas metabolism genes were upregulated."
"More than 40 androgen-regulated genes were affected"
40 of the 113 genes studied were androgen-regulated. Does this imply the presence of 40 transcription factors that include the androgen receptor?
FOXP1 is an androgen-responsive transcription factor that negatively regulates androgen receptor signaling in prostate cancer cells (PubMed)
Ref 15<114 on page 2<6 2008
"Androgen and androgen receptor (AR) play important roles in the formation and the progression of prostate cancer. AR activates its target genes by recruiting various coregulators and transcriptional factors. Here we show that the FOXP1 forkhead transcription factor is a novel androgen-regulated gene. By sequencing DNA fragments obtained from chromatin immunoprecipitation (ChIP), a bona-fide AR binding site (ARBS) is identified in an intron region of FOXP1 gene. FOXP1 can be induced by androgen in hormone-sensitive prostate cancer LNCaP cells at both mRNA and protein levels. ... we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region. We show that several other forkhead transcription factors are also androgen-responsive in LNCaP cells. Our study provides a new insight to the function of forkhead transcription factors that modulates AR signaling as an androgen-regulated transcriptional factor ..."
I don't really understand this.
1. "AR activates its target genes by recruiting various coregulators and transcriptional factors." This seems to enforce a clear distinction between the receptor and the transcription factor. I was thinking that the receptor was part of the transcription factor.
2. "... FOXP1 forkhead transcription factor is a novel androgen-regulated gene ... a bona-fide AR binding site (ARBS) is identified in an intron region of FOXP1 gene" So, is FOXP1 a transcription factor or a gene?
3. "FOXP1 can be induced by androgen in hormone-sensitive prostate cancer LNCaP cells at both mRNA and protein levels." What does 'induced' mean? Is the FOXP1 gene being transcribed by the FOXP1 transcription factor which includes the androgen receptor?
4. "We show that several other forkhead transcription factors are also androgen-responsive" Does this mean that these forkhead transscription factors contain an androgen receptor?
5. "... forkhead transcription factors that modulates AR signaling as an androgen-regulated transcriptional factor ..." If a transcription factor is 'androgen-regulated', does that mean that the androgen receptor is part of the transcription factor?
PubMed search for:
"mRNA synthesis testosterone-responsive genes"
Since reference  specifies testosterone in particular rather than androgens in general, I thought I'd repeat the search replacing "androgen" with "testosterone" and searching for "mRNA synthesis testosterone-responsive genes".
Surprisingly, I only got three hits, instead of 114, and none of them were useful.