The ETS family is a powerful family of transcription factors
and they are often found altered in prostate cancer. In this section we examine
a specific subset of these transcription factors.
The chart below displays the specific factors we discuss
herein. The driver for this discussion is a recent paper by Cheng et al which
discusses SPDEF and the regulation of FOXM1 oncogene. The paper is interesting
in that if examines a transcription factor and the specific influence on an
oncogene expression. SPDEF is in the ETS family and thus the interest in ETS. SPDEF
is the SAM pointed domain containing ETS transcription factor. Thus, the
acronym was formed. It is distinct from another ETS gene the PDEF which the
prostate derived epithelial factor. As they indicate it is not clear what the
role of SPDEF is in PCa and it is not clear whether its expression suppresses
or enhances PCa development. Yet the analysis of this process does present an
alternative view of a complex PCa development mechanism.
As Cheng et al have postulated the increase in SPDEF results
in a suppression of FOXM1 which is a known oncogene, especially for PCa. As in
Gellmann et al (pp 328-333) FOXM1 is a known oncogene. It drives the cell cycle
and thus leads to uncontrolled cell proliferation. We show this below:
The ETS (“E26 transformation specific”) family has some
30-40 genes and many relate to prostate cancer. For example the ERG (the “ETS
related gene”) gene is often found translocated with TPRSS in a fused state and
this translocation is a clear indication of an aggressive form of PCa. From Watson et al we have the following breath
of structure for the ETS family:
Let us begin with a brief overview of ETS family and
specifically the inclusion of SPDEF. As Wasylyk et al state:
The Ets family of transcription factors includes nuclear
phosphoproteins that are involved in cell proliferation, differentiation and
oncogenic transformation. The family is defined by a conserved DNA-binding
domain (the ETS-DBD), which forms a highly conserved, winged, helix-turn-helix
structural motif. As targets of the Ras-MAPK signaling pathway, Ets proteins
function as critical nuclear integrators of ubiquitous signaling cascades. To
direct signals to specific target genes, Ets proteins interact with (other)
transcription factors that promote the binding of Ets proteins to composite
Ras-responsive elements.
We demonstrate the winged or “butterfly” operation of ETS
transcription factors as shown below[1]:
In a 2012 report in Science Daily they state[2]:
Prostate cancer doesn't kill in the prostate -- it's the
disease's metastasis to other tissues that can be fatal. A University of
Colorado Cancer Center study published this week in the Journal of Biological
Chemistry shows that prostate cancer cells containing the protein SPDEF
continue to grow at the same pace as their SPDEF- cousins, but that these
SPDEF+ cells are unable to survive at possible sites of metastasis.
"It's as if these cancer cells with SPDEF can't chew
into distant tissue and so are unable to make new homes," says Hari Koul,
PhD, investigator at the CU Cancer Center and director of urology research at
the University of Colorado School of Medicine, the study's senior author.
Koul and his group discovered the homesteading power of
cancer cells that have lost SPDEF by introducing a gene into cells that makes
them glow in the presence of a dye, and then introducing them into the
bloodstream of animal models. Cells without SPDEF traveled through the blood
and successfully attached to tissue, surviving and so fluorescing many weeks
later when dye was introduced. However, cells with SPDEF flowed through the
blood but were unable to successfully establish new colonies and so soon died
out.
In fact, the protein SPDEF doesn't act directly to
allow cells to attach at possible metastasis sites, but is a transcription
factor that controls the production (or lack thereof) of two other proteins
MMP9 and MMP13. These two downstream proteins work to break down
tissue, like a dissolving agent -- they are the cleaning crew that clears space
for new and different growth, and in the case of prostate cancer metastasis
they chip the tissue footholds that cancer cells need to create
micrometastases.
There has been a great deal of work on MMPs especially MMP9[3]. We will expand this
discussion later.
"Given that MMP9 and perhaps MMP13 are also involved
in metastasis of several other cancers including lung, ovarian, breast and
colon to name a few, our findings could potentially have far-reaching
consequences outside prostate cancer," adds Koul
The group's continuing work points in two directions.
"First, we hope that the presence of SPDEF could
help doctors recognize prostate cancers that don't require treatment." If
future studies confirm the group's initial findings, the presence of SPDEF
could predict prostate cancers that are unable to metastasize and so unable to
kill. These cancers could be left to run their course without the use of
treatments that sometimes carry difficult side effects.
"And second," Koul says, "we hope to
regulate expression of this protein to remove prostate cancers' ability to
metastasize."
Koul points to small molecules, gene therapy or
nanodelivery as possible mechanisms for introducing SPDEF into cells that lack
the protein.
"With this discovery we have opened a hopeful door
into a future in which prostate and potentially other cancers are unable to
metastasize," Koul says.
However it appears that this work has been withdrawn in
several venues. It is not clear where the problem was that caused the
withdrawal.
We will now consider a recent
paper by Cheng et al which we referred to in the Introduction. The interest
here is the collecting together of multiple elements in this SPDEF chain and the
effects of ETS transcription factors.
In the recent paper by Cheng et al the authors state[4]:
SAM-pointed
domain-containing ETS transcription factor (SPDEF) is expressed in normal
prostate epithelium. While its expression changes during prostate
carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial
due to the lack of genetic mouse models. In present study, we generated
transgenic mice with the loss- or gain-of-function of SPDEF in prostate
epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate
cancer. Loss of SPDEF increased cancer progression and tumor cell
proliferation, whereas over-expression of SPDEF in prostate epithelium
inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in
vitro.
Transgenic
over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a
transcription factor critical for tumor cell proliferation, and reduced
expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2,
Plk-1, AuroraB, CKS1 and Topo2alpha.
Deletion of SPDEF in
transgenic mice and cultures prostate tumor cells increased expression of Foxm1
and its target genes. Furthermore, an inverse correlation between SPDEF and
Foxm1 levels was found in human prostate cancers. The two-gene signature of low
SPDEF and high FoxM1 predicted poor survival in prostate cancer patients.
Mechanistically, SPDEF bound to, and inhibited transcriptional activity of
Foxm1 promoter by interfering with the ability of Foxm1 to activate its own
promoter through auto-regulatory site located in the 2745/2660 bp Foxm1
promoter region. Re-expression of Foxm1 restored cellular proliferation in the
SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in
mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by
preventing Foxm1-regulated proliferation of prostate tumor cells.
The present study
identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene
and demonstrated that this crosstalk is required for tumor cell proliferation
during progression of prostate cancer in vivo.
The relationship between SPDEF and Foxm1 are significant and
could become a possible therapeutic target. They continue:
Development of
prostate cancer is a multistep process that involves the loss of tumor
suppressor functions and activation of oncogenes. SPDEF transcription factor is
expressed in normal prostate epithelium and its expression changes during
prostate carcinogenesis (PCa). Since the role of SPDEF in PCa remains
controversial, we generated transgenic mice with loss- and gain-of-function of
SPDEF to demonstrate that SPDEF functions as a tumor suppressor in PCa. In
animal models, the loss of SPDEF promoted PCa and increased the levels of
Foxm1, a well-known oncogenic protein.
Overexpression of
SPDEF in prostate epithelium decreased PCa and reduced Foxm1 levels.
Proliferation defects in SPDEF-containing tumor cells were corrected by
re-expression of Foxm1, providing direct evidence that SPDEF inhibits tumor
cell proliferation through Foxm1. We further showed that SPDEF directly bound
to Foxm1 promoter and prevented its autoregulatory activation. In prostate
cancer patients, the low SPDEF and high Foxm1 were found in most aggressive
prostate tumors that were associated with poor prognosis. The combined two-gene
signature of low SPDEF and high Foxm1 was a strong predictor of survival in
prostate cancer patients. The present study identified novel molecular
mechanism of prostate cancer progression, providing a crosstalk between SPDEF
tumor suppressor and Foxm1 oncogene.
Furthermore, Pal et
al in a paper, that has been subsequently withdrawn, had stated:
Loss of
E-cadherin is one of the key steps in tumor progression. Our previous studies
demonstrate that SAM pointed domain-containing ETS transcription factor (SPDEF)
inhibited prostate cancer metastasis in vitro and in vivo. In the present
study, we evaluated the relationship between SPDEF and E-cadherin expression in
an effort to better understand the mechanism of action of SPDEF in prostate
tumor cell invasion and metastasis.
The results
presented here demonstrate a direct correlation between expression of
E-cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that
modulation of E-cadherin and SPDEF had similar effects on cell
migration/invasion. In addition, siRNA-mediated knockdown of E-cadherin was
sufficient to block the effects of SPDEF on cell migration and invasion. We
also show that stable forced expression of SPDEF results in increased
expression of E-cadherin, whereas down-regulation of SPDEF decreased E-cadherin
expression.
In addition, we
demonstrate that SPDEF expression is not regulated by E-cadherin. Moreover, our
chromatin immunoprecipitation and luciferase reporter assay revealed that SPDEF
occupies E-cadherin promoter site and acts as a direct transcriptional inducer
of E-cadherin in prostate cancer cells. Taken together, to the best of our
knowledge, these studies are the first demonstrating requirement of SPDEF for
expression of E-cadherin, an essential epithelial cell junction protein. Given
that loss of E-cadherin is a central tenant in tumor metastasis, the results of
our studies, by providing a new mechanism for regulation of E-cadherin expression,
could have far reaching impact.
The SPDEF capability to deal with adhesion via the paths
shown is a significant factor in its overall importance in metastasis.
Foxm1 is a transcription activator and can be silenced by
SPDEF. However when SPDEF is deficient then Foxom1 can act as an aggressive
oncogene and can press metastatic growth.
From NCBI we have[7]:
The protein encoded by this gene is a transcriptional
activator involved in cell proliferation. The encoded protein is phosphorylated
in M phase and regulates the expression of several cell cycle genes, such as
cyclin B1 and cyclin D1. Several transcript variants encoding different
isoforms have been found for this gene.
The Foxm1 gene may be a therapeutic target. It pushes the
cell through the cell cycle and can kick off aggressive metastatic growth. This
simple connection between the regulatory role of SPDEF and the aggressive cell
cycle capabilities of Foxm1 is an important observation.
MMP genes have been found to assist metastatic growth by
degrading the ECM structures. As Chiang et al state:
Various members of the matrix metalloproteinase (MMP)
family (e.g., MMP-2 and MMP-9) are also implicated in cancer cell invasion.
Independent screens for genes that mediate bone or lung metastasis in breast
cancer have identified MMP-1 as being necessary for spread to the bone and
lungs.
As noted in NCBI:
Proteins of the matrix metalloproteinase (MMP) family are
involved in the breakdown of extracellular matrix in normal physiological
processes, such as embryonic development, reproduction, and tissue remodeling,
as well as in disease processes, such as arthritis and metastasis. Most MMP's
are secreted as inactive proproteins which are activated when cleaved by extracellular
proteinases. The enzyme encoded by this gene degrades type IV and V collagens.
Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced
mobilization of hematopoietic progenitor cells from bone marrow, and murine
studies suggest a role in tumor-associated tissue remodeling.
MMP actions are shown below in general terms depicting the
activation via the ERB pathway:
MMPs initiate their actions via ECM degradation first and
then enable cell migration and sustainability via angiogenesis. Thus the
evidence of MMP-9 and MMP-14 are significant. As Marks et al note (p 242) there
is no known ligan for ErbB2 but it does form an active heterodimer with either
ErbB1 or ErbB4. We examine that pathway shortly. Also Marks et al note (p 243)
that the organization of the ErbB network is quite complex and demands a
systems based approach. This “systems based approach” is essential as we
consider the interaction of all of these elements.
The details of the ErbB2 pathway are shown below:
Although the paper in question regarding SPDEF does read
onto the MMPs directly the discussing surrounding it does.
In a 2012 paper by Stefan et al[8]:
The role of SPDEF in tumor biology
remains hotly debated. SPDEF suppressed tumor metastasis
in-part by modulating MMP9 and MMP13. SPDEF is a modifiable therapeutic target
in prostate tumors. This is the first study directly implicating SPDEF as a
tumor metastasis suppressor in any system in vivo. Emerging evidence suggests
that SAM Pointed Domain Containing ETS Transcription Factor (SPD
EF), plays a significant role in
tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there
are no in vivo studies with respect to the role of SPDEF in tumor metastasis.
The present study examined the effects of SPDEF on tumor cell metastasis using
prostate tumor cells as a model. Utilizing two experimental metastasis models,
we demonstrate that SPDEF inhibits cell migration and invasion in vitro and
acts a tumor metastasis suppressor in vivo.
Using stable expression of SPDEF in
PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we
demonstrate for the first time that SPDEF diminished the ability of
disseminated tumors cells to survive at secondary sites and establish
micrometastases. These effects on tumor metastasis were not a result of the
effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth
in vitro, or subcutaneous tumor xenograft-growth in vivo. Transcriptional
analysis of several genes associated with tumor metastasis, invasion, and the
epithelial-mesenchymal transition demonstrated that SPDEF overexpression
selectively down-regulated MMP9 and MMP13 in prostate cancer cells.
Further analysis indicated that forced
MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3
cells in vitro, suggesting that the effects of SPDEF on tumor invasion are
mediated, in part, through the suppression of MMP9 and MMP13 expression. These
results demonstrate for the first time, in any system, that SPDEF functions as
a tumor metastasis suppressor in vivo.
From Science Daily they state[9]:
Prostate cancer
doesn't kill in the prostate -- it's the disease's metastasis to other tissues
that can be fatal. A University of Colorado Cancer Center study published this
week in the Journal of Biological Chemistry shows that prostate
cancer cells containing the protein SPDEF continue to grow at the same pace as
their SPDEF- cousins, but that these SPDEF+ cells are unable to survive at
possible sites of metastasis.
"It's as if these cancer cells
with SPDEF can't chew into distant tissue and so are unable to make new
homes," says Hari Koul, PhD, investigator at the CU Cancer Center and
director of urology research at the University of Colorado School of Medicine,
the study's senior author.
Koul and his group discovered the
homesteading power of cancer cells that have lost SPDEF by introducing a gene
into cells that makes them glow in the presence of a dye, and then introducing
them into the bloodstream of animal models. Cells without SPDEF traveled
through the blood and successfully attached to tissue, surviving and so
fluorescing many weeks later when dye was introduced. However, cells with SPDEF
flowed through the blood but were unable to successfully establish new colonies
and so soon died out.
In fact, the protein SPDEF doesn't act
directly to allow cells to attach at possible metastasis sites, but is a
transcription factor that controls the production (or lack thereof) of two
other proteins MMP9 and MMP13.
These two downstream proteins work to
break down tissue, like a dissolving agent -- they are the cleaning crew that
clears space for new and different growth, and in the case of prostate cancer
metastasis they chip the tissue footholds that cancer cells need to create
micrometastases. "Given that MMP9 and perhaps MMP13 are also involved in
metastasis of several other cancers including lung, ovarian, breast and colon
to name a few, our findings could potentially have far-reaching consequences
outside prostate cancer," adds Koul
The group's continuing work points in
two directions. "First, we hope that the presence of SPDEF could help
doctors recognize prostate cancers that don't require treatment." If
future studies confirm the group's initial findings, the presence of SPDEF
could predict prostate cancers that are unable to metastasize and so unable to
kill.
These cancers could be left to run
their course without the use of treatments that sometimes carry difficult side
effects.
"And second," Koul says,
"we hope to regulate expression of this protein to remove prostate cancers' ability to metastasize." Koul
points to small molecules, gene therapy or nanodelivery as possible mechanisms
for introducing SPDEF into cells that lack the protein.
"With this discovery we have
opened a hopeful door into a future in which prostate and potentially other
cancers are unable to metastasize," Koul says.
From Stefan et al (2011)
the authors had stated the following about another ETS transcription factor,
PDEF, not to be confused with SPDEF. :
The prostate-derived ETS factor (PDEF) is the
latest family member of the ETS transcription factor family, although it is
unique in many aspects. PDEF was first described as an mRNA transcript highly
expressed in prostate tumor cells where it regulates prostate-specific antigen
gene expression and is an androgen receptor co-regulator.
PDEF expression is highly restricted to
epithelial cells and has only been found in prostate, breast, colon, ovary,
gastric, and airway epithelium. Strong preclinical evidence is emerging that
PDEF is a negative regulator of tumor progression and metastasis. PDEF
expression is often lost in late-stage, advanced tumors.
The induction of tumor aggressiveness in
response to the loss of PDEF is thought to be due to the plethora of
PDEF-regulated gene targets, many of which are known players in tumor
progression including tumor cell invasion and metastasis. These data have led
to the hypothesis that PDEF may function as a tumor metastasis suppressor.
In this review, we summarize what is known
about PDEF since its discovery over a decade ago and give a detailed overview
of PDEF-regulated gene products and the expression profiles of PDEF in clinical
tumor samples.
Thus many other ETS
transcription factors have similar roles. The therapeutic targeting of these
factors may be of significant merit.
The analysis of
SPDEF is interesting especially because it raises so many other issues.
1. SPDEF deals with
multiple other pathway elements from receptors to promoter factors and the
resulting complex pathway interactions demonstrate the need for having a
complete systems model.
2. No clear
therapeutic targets seem to be evident. Although the results are compelling the
complexity of the pathways and their interactions lead one to examine more
specific control points, since SPDEF by itself seems to be a multiple set of
paths leading to metastasis.
3. There is the
question of whether SPDEF can be prognostic and/or therapeutic. Many of the
prognostic tests use large banks of gene expressions to develop a single
metric. Oftentimes this metric can be useful but it also does not per se
reflect what process is defective and what cells are the most of concern. The
problem is that all too often when one samples a section of tumor that the
cells may have substantially different gene expression profiles. We have examined
technologies that allows the sampling of individual cells and creating a
profile of the tumor in broad profile terms, namely how many cells express what
genes (mRNA or proteins) and from that ascertaining prognostic measures.
4. The complexity of
the relationships between the ETS transcription factor SPDEF, the oncogene
Foxm1 and the MMD metastatic facilitators is of interest. It demonstrates a
“system” view of the cancer. The key questions are; when does this occur, in
what percent of the cells does this occur, and what is its prognostic value?
1.
Aronson, B., et al, Spdef
deletion rescues the crypt cell proliferation defect in conditional Gata6 null
mouse small intestine, BMC Molecular Biology 2014, 15:3
2.
Carver et al, ETS
rearrangements and prostate cancer initiation, NATURE| Vol 457| 12 February
2009, http://www.nature.com/nature/journal/v457/n7231/abs/nature07738.html
3.
Cheng, X, et al, SPDEF Inhibits Prostate Carcinogenesis by Disrupting a
Positive Feedback Loop in Regulation of the Foxm1 Oncogene, PLOS Genetics,
September 2014 | Volume 10 | Issue 9 , J. Biol. Chem. http://www.jbc.org/content/289/32/22020.full.pdf+html
(Withdrawn)
4.
Chiang, A., J. Massagué, Molecular
Basis of Metastasis, NEJM, V 359 2814-2823 2008.
5.
Davuluri, G., et al,
WAVE3-NFkB Interplay Is Essential for the Survival and Invasion of Cancer
Cells, PLOS ONE, www.plosone.org, 1
October 2014, Volume 9, Issue 10, e110627.
6.
Gelmann, E., Molecular
Oncology, Cambridge (New York) 2014.
7.
Deutsch, E., et al,
Environmental, genetic, and molecular features of prostate cancer, THE LANCET
Oncology Vol 5 May 2004.
8.
Jamaspishvili, T., et al, Urine
markers in monitoring for prostate cancer, Prostate Cancer and Prostatic
Diseases (2010) 13, 12–19
9.
Kalin, T., et al, Increased
Levels of the FoxM1 Transcription Factor Accelerate Development and Progression
of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice, Cancer Res. 2006
February 1; 66(3): 1712–1720.
10. Marks, F., et al, Cellular Signal Processing, Garland (New York)
2009.
11. Mintu Pal, Sweaty Koul and Hari K. Koul, (SAM) pointed
domain-containing ETS transcription factor (SPDEF) is required for E-cadherin
expression in prostate cancer cells, 2014, 289:22020.
12. Pal, M., et al, The Transcription Factor Sterile Alpha Motif
(SAM) Pointed Domain-containing ETS Transcription Factor (SPDEF) Is Required
for E-cadherin Expression in Prostate Cancer Cells, http://www.jbc.org/content/288/17/12222.long
April 26, 2013 The Journal of Biological Chemistry, 288, 12222-12231.
(Withdrawn)
13. Pestel, R., M. Nevalainen, Prostate Cancer, Humana, 2008.
14. Penny, K., et al, Association of KLK3 (PSA) genetic variants
with prostate cancer risk and PSA levels, Carcinogenesis vol.32 no.6
pp.853–859, 2011.
15. Riley, T., et al, Transcriptional control of human p53-regulated
genes, Nature Reviews Molecular Cell Biology, Volume 9, May 2008.
16. Schrecengost, R., K, Knudsen, Molecular Pathogenesis and Progression
of Prostate, Seminars in Oncology, Vol 40,No3, June2 013, pp244-258.
17. Stefan, J., et al,
Prostate derived ETS factor (PDEF): a putative tumor metastasis suppressor,
Cancer Lett. 2011 Nov 1; 310(1):109-17. Epub 2011 Jun 29.
18. Stefan, J., et al, The
transcription factor SPDEF suppresses prostate tumor metastasis, First
Published on July 2, 2012, doi: 10.1074/jbc.M112.379396 jbc.M112.379396. JBC.
19. Tomlins, S., et al, ETS
Gene Fusions in Prostate Cancer: From Discovery to Daily Clinical Practice,
European Urology, 2009. doi:10.1016/j.eururo.2009.04.036
20. Turner, D., The Role of ETS Transcriptional Regulation in
Hormone Sensitive and Refractory Prostate Cancer, The Open Cancer Journal,
2010, 3, 40-48.
21. Turner, D., et al, Mechanisms and functional consequences of
PDEF protein expression loss during prostate cancer progression, Prostate. 2011
December; 71(16): 1723–1735. doi:10.1002/pros.21389.
22. Watson, D., et al, ETS Transcription Factor Expression and
Conversion During Prostate and Breast Cancer Progression, The Open Cancer
Journal, 2010, 3, 24-39
23. Wasylyk B1, Hagman J, Gutierrez-Hartmann A., Ets transcription
factors: nuclear effectors of the Ras-MAP-kinase signaling pathway. Trends
Biochem Sci. 1998 Jun; 23(6):213-6.
24. Yordy, J. and Robin C Muise-Helmericks, Signal transduction and
the Ets family of transcription factors, Oncogene (2000) 19, 6503 http://www.nature.com/onc/journal/v19/n55/pdf/1204036a.pdf
[1]
See Marks et al p 405. As adapted.
[3]
See Jamaspishvili et al, Matrix metalloproteinases (MMPs) have been
implicated in invasion and metastasis of human malignancies. Moses et al. used
substrate gel electrophoresis (zymography) to determine MMPs in the urine of
patients with a variety of cancers. MMP9 yielded better sensitivity (64%) than
MMP2 (39%) for CaP whereas specificities (84 and 98%, respectively) were
calculated from controls of both sexes. The same group also detected several
unidentified urinary gelatinase activities with molecular weights 4125 kDa and
recently used chromatography, zymography and mass spectrometry for their
identification. The approximately 140, 4220 and approximately 190 kDa
gelatinase species were identified as MMP9/TIMP1 complex, MMP9 dimer and
ADAMTS7, respectively. MMP9 dimer and MMP9 were independent predictors for
distinguishing between patients with prostate and bladder cancer.
[5] From NCBI: The
androgen receptor gene is more than 90 kb long and codes for a protein that has
3 major functional domains: the N-terminal domain, DNA-binding domain, and
androgen-binding domain. The protein functions as a steroid-hormone activated
transcription factor. Upon binding the hormone ligand, the receptor dissociates
from accessory proteins, translocates into the nucleus, dimerizes, and then
stimulates transcription of androgen responsive genes. This gene contains 2
polymorphic trinucleotide repeat segments that encode polyglutamine and
polyglycine tracts in the N-terminal transactivation domain of its protein.
Posts
