over the last few years , the involvement of the proteasome pathway in ligand - dependent nuclear receptor degradation has been established . this pathway entails first a polyubiquitination of the substrate , catalyzed by three factors ( e1 , e2 and e3 ) , followed by its proteolysis by the proteasome . recently , the role of the csn complex that regulates the activity of a class of e3 ubiquitin ligases , the cullin ring ubiquitin ligase superfamily , was demonstrated . the cullin subunits of these ubiquitin ligases are modified by the conjugation of an ubiquitin - like protein , nedd8 . recent data demonstrate that csn , via its subunit csn5/jab1 , dennedylates cullin , thus increasing the activity of the e3 ligases [ wee et al . , several lines of evidence suggest that csn is involved in ligand - dependant nuclear receptor degradation . first , estrogen receptor  ( er ) degradation is dependant on the neddylation pathway [ fan et al . , 2003 ] ; second , csn5/jab1 interacts with both the progesterone receptor and the coactivator src1 and is itself a coactivator of the nuclear receptors [ fan et al . , 2003 ] ; third , jab1/csn5 increases hormone - induced er degradation [ fan et al . , the nature of the ligand affects er degradation differently : estradiol and the pure antagonist fulvestrant induce er degradation by the proteasome , whereas the mixed antagonist tamoxifen stabilizes er [ wijayaratne and mcdonnell , 2001 ] . thus , degradation may play an important role in er function and/or the action of its antagonists . er undergoes post translational modifications such as phosphorylation [ lannigan , 2003 ] , acetylation [ wang et al . , at least two curcumin - sensitive kinases , ckii and pkd , which co - purify with csn , could contribute to this activity [ uhle et al . the inhibition of er degradation by curcumin and the co - immunoprecipitation of jab1/csn5 with er in the presence of curcumin , suggest that this kinase activity could participate in targeting er for degradation . in addition , the inhibition by curcumin of the interaction of er with its dna target , points towards a role of this complex in transcription activation [ callige et al . , the discovery that e2 and e3 factors and proteasome subunits associate with the transcriptional machinery , reinforces the hypothesis that the degradation of nuclear receptors could be linked to transcriptional activation and may be necessary for efficient transcriptional activity [ nawaz and o'malley , 2004 ] . here we discuss er degradation pathways in the presence of different ligands and the role of this degradation in er function . the demonstration that the nedd8 pathway is required for proteasome mediated degradation of er , suggests that the e3 ligases involved belong to the cullin ring ubiquitin ligase superfamily . within this family , mdm2 and e6-ap , were identified as er coactivators [ nawaz et al . , 1999 ; saji et al . , mdm2 is also involved in the degradation of glucocorticoid and androgen receptors [ kinyamu and archer , 2003 ; lin et al . , er could also be a substrate for brca1/bard1 , another potential e3 ligase , which is recruited by phospho - pol ii and is involved in the degradation of both chromatin proteins and active rna polymerase ii [ starita and parvin , 2003 ] . one could speculate its involvement in er degradation since this degradation is concomitant with transcriptional activation . however brca1/bard1 belongs to the hect e3 ligase family , and there is no evidence that the need8 pathway regulates its activity . transcription activation by er involves a number of co - regulators , in particular coactivators of the p160 family ( src1/src2/src3 ) . the activity of src3 ( the major er coactivator in breast cancer cell lines ) is regulated by phosphorylation [ wu et al . , hormone - induced transcription requires the dissociation of a corepressor ( n - cor / smrt ) from er and its replacement by a coactivator from the p160 family . tblr1 , a protein that shares homology with tbl1 ( transducin-like1 ) , selectively mediates corepressor / coactivator exchange upon ligand binding to nuclear receptors [ perissi et al . , 2004 ] . several observations converge towards a link between the recruitment of er cofactors and ligand - dependent degradation by the proteasome . suppression of src3/aib1 by sirna leads to er stabilization in presence of estradiol [ shao et al . , 2004 ] and src3/aib1 itself is degraded by the proteasome in a hormone - dependent process [ perissi et al . , nuclear receptor co - factors such as tbl1 and tblr1 ( originally identified as components of an n - cor complex ) , besides their er-cofactor exchange activity , serve as specific adaptors for the recruitment of the conjugating/19s proteasome complex and thus participate in co - factor dynamics at the promoter during the transcription initiation process [ perissi et al . , inhibition of crm1-dependent nuclear export by leptomycin b blocks estrogen - dependent , but not fulvestrant - induced degradation of er. this demonstrates that the two ligands induce er degradation through different pathways , taking place in different cellular compartments . in the presence of estradiol er is degraded by a cytoplasmic fraction of the proteasome , whereas in the presence of fulvestrant it is degraded in the nucleus [ callige et al . , these findings reinforce observations demonstrating rapid sequestration of the er-fulvestrant complex in a salt - insoluble , nuclear compartment [ giamarchi et al . , 2002 ] and reduced mobility of the er-fulvestrant complex relative to the estradiol - er complex in the nucleus [ stenoien et al . , the fact that fulvestrant is unable to promote either chromatin remodeling over the tff1 estrogen - regulated promoter [ giamarchi et al . , 2002 ] , or binding of er to its dna target within the same promoter [ reid et al . , 2003 ] , indicates that the nuclear sub - compartment in which the fulvestrant - er complex is degraded , must be distinct from the sub - compartment in which transcription takes place . the nature of the nuclear compartment in which this degradation takes place remains unknown . to understand better the mechanism of action of the pure antiestrogen fulvestrant , several issues need to be elucidated : what is the nature of the compartment in which er is sequestered ? does fulvestrant play a direct role in such targeting , e.g. , by directly recruiting a cofactor that changes the fate of er-fulvestrant complex ? do corepressors or coactivators play a role in this process ( as suggested by the fact that suppression of src3/aib1 by sirna leads to er stabilization in presence of estradiol but not of fulvestrant ) [ shao et al . , the pathways involved in er degradation differ , depending on the ligand ( hormone or full antagonist , such as fulvestrant ) . a phosphorylation event catalysed by a curcumin - sensitive kinase , that could be ckii , is necessary for both estradiol- and fulvestrant - induced er degradation [ callige et al . , 2005 ] , making it unlikely that this phosphorylation plays a role in the targeting of er to different degradation - compartments . the exact role of src3/aib1 in each step of the hormone - induced er degradation process remains to be determined . the fact that er-oh - tamoxifen complex ( that can not recruit coactivators ) is not released from target promoters [ wijayaratne and mcdonnell , 2001 ] , along with the observations that src3 is co - degraded with er [ shao et al . , 2004 ] and that suppression of   src3 expression abrogates er degradation [ lonard et al . , a possible role of the csn in src3/aib1 phosphorylation and degradation should be investigated . figure 1 presents a model summarizing the different steps that may be involved in estradiol - induced er degradation and the possible links with transcription activation . er-hormone complex interacts with a coactivator ( src3/aib1 in breast cancer cells ) and with csn5/jab1 . er and/or src3/aib1 are phosphorylated by a curcumin - sensitive kinase , possibly associated with the csn , leading to the binding of er to promoters of estrogen regulated genes . curcumin prevents such binding either because er or src3/aib1 phosphorylation is required for dna binding , or because phosphorylation is required for a stable interaction between er and src3/aib1 . upon transcription initiation , exchange factors such as tbl1 or tblr1 should facilitate recruitment of coactivators by er and of ubiquitin ligase factors at the promoter . er and/or src3/aib1 may be tagged for degradation as a result of a post - translational modification and/or a polyubiquitination . leptomycin b inhibits er degradation and increases hormone dependent transcription , suggesting that the modifications ( putative tagging and/or polyubiquitination ) can be reversed and the complex recycled . the csn could be involved at that step through the recruitment of a deubiquitinating enzyme . in the cytoplasm , a first set of results suggests that er degradation is required to sustain transcription [ lonard et al . , 2000 ; reid et al . , 2003 ] , yet another set concludes that er degradation has no general direct effect on transcription [ alarid et al . , 2003 ; callige et al . , 2005 ; fan et al . , 2003 ] . it should be noted that the experiments suggesting that er degradation is required to sustain transcription , used treatment times with proteasome inhibitors or drb , for longer than 12 hours [ lonard et al . , 2000 ; such a long treatment time may have pleiotropic effects on the cell and affect multiple components of the transcription machinery . in contrast , the experiments suggesting that er degradation has no influence on transcription , used much shorter treatment times ( less than 3 hours ) , minimizing general effects of the inhibitors used . er degradation seems rather to be the consequence of transcription initiation , as shown by the inhibitory effect of curcumin , rather than transcription per se , since drb that blocks transcription does not prevent hormone - dependent er degradation [ alarid et al . in addition , the nature of the transcription factors recruited , along with er , as well as the architecture of each promoter seem to be important , suggesting that the effect of proteasome inhibitors on transcription results from the degradation of co - regulators , rather than from that of er [ callige et al . , 2005 ; fan et al . , 2003 ] . whatever the role er degradation plays at the molecular level of transcription activation , ligand induced er degradation may be of importance at the physiological level . estradiol forms a stable complex with er. this hormone - receptor complex should sustain transcription for extended periods of time . degradation of the er-hormone complex at each round of transcription could be a way for the cell to fine tune transcription activation in response to rapid changes in hormone concentration .