Androgens in Health and Disease.pdf - E Library

160 Marcelli et al.
These coactivator proteins typically interact with the receptor through either the amino
terminal or the carboxyl terminal, serving as bridges between the receptor and the
proteins of the transcription complex. This is an active area of research and the number
of coactivators and the activities associated with them is expanding rapidly. Current
models suggest that coactivators form complexes of multiple proteins, some of which
have intrinsic enzyme activities that enhance transcription (reviewed in ref. 26). One
of the most important coactivator functions is the histone acetyltransferase (HAT)
activity that facilitates acetylation of histones that are bound to target genes and that
open chromatin structure (27).
The coactivators can be broadly categorized into three groups: (1) those that modulate
the activity of a wide variety of transcription factors, (2) those that stimulate the activity
of nuclear receptors and few if any other transcription factors, and (3) those that activate
one or a few of the nuclear receptors.
CREB-binding protein (CBP) is a coactivator that falls in the group of coactivators
that modulate a wide variety of transcription factors. First described as a protein that
modulates the activity of cAMP-response elements binding protein (CREB) (28), CBP
serves as a coactivator for AR, as well as for other nuclear receptors.
The p160 family of coactivators is an example of those coactivators that interact
with most, if not all, nuclear receptors. The nearly simultaneous discovery of the
coactivators in different species and the existence of a number of splice variants have
led to numerous names for closely related proteins. Three genes have been identified
in this family. The first was SRC-1 (29) also called NcoA-1, followed by the other
p160 coactivator family members, TIF2/GRIP (SRC-2) (30,31) and p/CIP/RAC3/
ACTR/AIB-1/TRAM (SRC-3) (32–34). These proteins interact in an agonist-dependent
manner with the hormone-binding domains of steroid receptors through LXXLL
motifs within the coactivators (26). Subsequent studies revealed that there are also
substantial interactions with the amino-terminal activation domains of the nuclear
receptors. In the case of the androgen receptor, several studies suggest that the most
important interactions with AR occur through the amino-terminal domain (35,36).
Some of these coactivators are, themselves, HATs, and they recruit P/CAF, another
HAT, enhancing histone acetylation at target genes (26).
A plethora of other proteins have been identified that interact with AR and enhance
transcriptional activity. In some cases, the specificity of their actions remains to be
determined. These include the androgen-receptor-associated (ARA) proteins identified
by Chang’s group by yeast two hybrid screening as interacting either with the hormonebinding
domain or with the N-terminus. Many of these proteins have been cloned previously,
and their alternate names are included in parentheses. The ARA proteins include
ARA70 (RFG, ELE1), ARA55 (hic5), ARA54, and ARA24 (a Ras-related nuclear protein)
(37–40). Other candidates include retinoblastoma protein (Rb) (41), SNURF (small
nuclear ring finger protein) (42), Tip60 (also a coactivator for human immunodeficiency
virus TAT protein) (43), CAK (cdk-activating kinase) (44), and FHL2 (DRAL) (44). The
relative contributions of these proteins to AR action remain to be determined. Some
coactivators enhance each other’s activity, whereas others appear to be redundant, as the
proteins can substitute for each other. These roles will be clarified as mice null for one
or more of the coactivators are produced. The SRC-1-null mouse exhibits a reduction in
size/development of a number of reproductive tissues, including the prostate, suggesting
that it plays a role in vivo in the activity of the reproductive hormone receptors (45).