Numerous cellular targets of SUMO targets modulate transcription. Steroid receptors such as ARs, which are ligandregulated transcription factors belonging to the nuclear receptor superfamily [44
], have been reported as SUMO-ylated proteins. ARs are sumoylated in vivo
at lysine residues 386 and 520 [21
]. Mutation of these residues increases the transactivation ability of ARs, suggesting that sumoylation is involved in the repression of AR activity [21
c-Jun is a transcription factor that plays an important role in regulating cell growth, apoptosis, differentiation, and transformation. The transcriptional activity of c-Jun can be regulated by both phosphorylation and sumoylation. c-Jun is conjugated by SUMO at amino acids 229 and 257, with sumoylation negatively regulating c-Jun-dependent transcription [33,45
It is well known that both ARs and c-Jun interact with various coregulatory proteins; this interaction can regulate the transcriptional activity of nuclear receptors and transcription factors.
Recently, it has been found that four AR coregulators are sumoylated. These AR coregulatory proteins either transactivate or transrepress AR transcriptional activity by binding the specific functional domains of receptors (the N-terminal transactivation region, the central DNA-binding domain, and the C-terminal ligand-binding domain). The transactivator SRC1, for example, has five sumoylation sites, and two major sites are localized in a nuclear receptor box situated in the nuclear receptor-interacting region 1 [22
]. It was observed that sumoylation could increase the interaction of SRC1 with progesterone receptors. For the coactivator GRIP1, two residues located in the nuclear receptor-interacting region were found to be sumoylated [46
]. Substitution of these two sumoylation sites could attenuate the activity of GRIP1 on AR-dependent transcription. The transrepressors HDAC1 and HDAC4 were also found to be sumoylated [25,47,48
]. Mutation of the two sumoylation sites of HDAC1 profoundly reduced HDAC1-mediated transcriptional repression [25
]. An HDAC4 sumoylation mutant showed a slightly impaired ability to repress transcription, as well as reduced HDAC activity [28
Similarly, p300 is a well-known coactivator of c-Jun [49–52
] that has been shown to physically interact with c-Jun and to activate c-Jun-dependent transcription [50
]. Because the transcriptional activity of p300 can be modulated by a number of signaling pathways, p300 provides an additional level of regulation for c-Jun-dependent transcription.
It has been reported that p21 regulates p300 transcriptional activity [53–55
]. p21 not only inhibits p300-bound cyclin E-Cdk2 activity through repression of the histone acetyltransferase activity of p300 [56
] but also stimulates p300 transactivation [55
]. Within p300, a domain named CRD1 has been identified as a domain with strong transcriptional repression [55
]. CRD1 functions independently of p300 histone acetyltransferase domains, but can repress the transactivational activity of p300 [55
]. p21 derepresses this CRD1 activity and, thus, selectively activates p300-dependent transcription at specific promoters. Recent findings indicate that sumoylation is required for CRD1-dependent transcriptional repression [24
]. The two SUMO modification sites within the CRD1 domain of p300 have been identified, and mutation at these two sites can reduce the repression of CRD1 domain and p21 inducibility [24
]. Therefore, SUMO modification provides a new mechanism to control p300 function and potentially novel mechanisms for the regulation of c-Jun-dependent transcriptional activities.
As ARs, c-Jun, and coregulatory proteins are sumoylated, we believe that SENPs will play an important role in regulating AR and c-Jun activity through the deconjugation of sumoylated coregulators (see below).