the role of ligand in the interaction of androgen receptor with dna ...

In summary, in addition to the ligand, sumoylation is emerging as an important control
mechanism in the regulation of subcellular targeting and interactions of steroid receptors and
their coregulators (Figure 16).
SNURF
NUCLEUS
GRIP1
AGONIST
PML
SUMO
GRIP1
POL II
POL II
PML
PML
PML GRIP1
PURE
ANTAGONIST
AR domain
PML
PML
PML
PML nuclear domain, ND10
GRIP1
POL II
POL II
AR and GRIP1
colocalizing at
transcription site
NuMA attached ARs
Fig. 16. Schematic summary of AR and coregulator trafficking. In principle, the ligand regulates the following AR
functions: AR trafficking to the nucleus, DNA binding, transcription activation function, interaction with
coregulators and the residence of AR in “AR speckles”. Agonistic ligands support all the aforementioned functions,
but pure antagonist, hydroxyflutamide and casodex, block DNA binding, transactivation and interaction with
coactivator GRIP1. GRIP1 is distributed either diffusely in the nucleoplasm, in granular domains, in ND10s with
PML or in SR domains. Sumoylation of GRIP1 may be an important element for both modulation of AR-dependent
transcription and colocalization with AR. Agonist-occupied AR colocalizes with correctly sumoylated GRIP1 at
transcription sites in a speckled pattern typical of AR domains. Sumoylation regulates the formation and
composition of ND10s and interactions of PML body proteins. PML bodies may be involved in the regulation of SR
activity through their ability to regulate p160 proteins. Another coregulator, SNURF, is able to facilitate AR
trafficking into the nucleus and association of AR with the nuclear matrix (NuMa). The functions that we have
examined in this study are indicated with black arrows, other interactions that are known to be important for the
regulation of AR and GRIP1 function and the residence in nuclear domains are depicted with white arrows. In
addition to ligand- and sumoylation-dependent regulation, SR activity is also regulated by ubiquitinylation.
Degradation of SRs is ubiquitinylation-dependently regulated, and sumoylation has been shown to antagonize
ubiquitinylation-dependent degradation of some proteins. Interestingly, SNURF is an ubiquitin ligase.
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