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nuclear receptor ( nr ) mediated gene activation or repression is regulated by the cellular context of transcriptional coactivators and corepressors ( cors ) [ cheng , 2000 ; glass and rosenfeld , 2000 ; mckenna and o'malley , 2002 ] . due to the complexity of endogenous nr coregulators in mammalian cells
it is difficult to determine the precise mechanisms by which nr coactivators and corepressors function .
the budding yeast saccharomyces cerevisiae contains the conserved eukaryotic general transcriptional apparatus and chromatin remodeling enzymes , but is devoid of nuclear receptors and their coregulators ( see [ anafi et al . , 2000 ;
it becomes possible to measure qualitatively and quantitatively the functions of exogenous cofactors by reconstituting desired combinations of factors in isolation from the bewildering effects of a myriad of endogenous competing factors .
our previous studies have proved that two types of human thyroid hormone receptor ( htr ) coactivation pathways can be reconstituted in the yeast saccharomyces cerevisiae .
firstly , p160 proteins , such as grip1 and src1 , which contain lxxll motifs necessary for hormone dependent interaction with the tr [ heery et al . , 1997 ; torchia et al . ,
1997 ] , require thyroid hormone ( th ) and the saga adaptor protein complex to function [ anafi et al . , 2000 ] .
this pathway is akin to tr coactivation pathways that have been extensively studied in mammalian systems [ cheng , 2000 ; glass and rosenfeld , 2000 ] and functions through the intrinsic acetyltransferase activity of the saga adaptor complex [ anafi et al . , 2000 ] .  
secondly , human adenovirus type 5 early region 1a ( e1a ) protein behaves as a th independent tr coactivator in yeast and does not require gcn5 or other components of saga [ meng et al . ,
interestingly , coactivation of tr dependent transcription by e1a is lost upon addition of hormone through a ligand induced loss of e1a - tr interaction [ meng et al . ,
hormone - dependent loss of e1a - tr interaction is reminiscent of tr interactions with nuclear receptor corepressors such as n - cor and smrt , which interact with unliganded tr and with other nrs in the absence of hormone or in the presence of antagonists [ cheng , 2000 ; glass and rosenfeld , 2000 ] .
the corepressors contain nr interacting domains that share a core consensus motif : xx ( where  is a hydrophobic residue and x is any amino acid ) that comprise part of the extended consensus lxxi / hixxxi / l cornr box motif ( cbm ) [ hu and lazar , 1999 ] .  
these motifs are believed to encode an extended amphipathic helix which contacts the same hydrophobic pocket that binds lxxll motifs , but is not dependent on the charge clamp and the af2 helix [ hu and lazar , 1999 ; perissi et al . , 1999 ] .  
this configuration has been confirmed in an x - ray crystal structure of peroxisome proliferator activated receptor  in complex with an antagonist and a smrt cbm peptide [ xu et al . ,
inspection of e1a identified a short sequence ( ldqlieevl amino acids 20 - 28 ) that strongly resembles a cbm and this was shown to be necessary for tr binding and coactivation , and to bind the same tr surface as corepressors [ meng et al .
thus , a viral protein has co - opted a cellular protein interaction motif to target the unliganded tr . although e1a binding to unliganded tr mimics that of corepressors , the end result is to confer constitutive coactivation function .
the interaction of e1a with tr in the absence of th exemplifies the economical nature of adenovirus e1a to stoichometrically affect target protein function [ frisch and mymryk , 2002 ] .
clearly , if the purpose of the interaction of e1a with the unliganded tr is to activate transcription , there is no need for e1a to bind the tr in the presence of hormone and duplicate the function of existing cellular coactivators .
this is highly reminiscent of the interaction of e1a with prb , which regulates exit from the g1 phase of the cell cycle . in this case ,
e1a binds the hypophosphorylated form of prb , which is actively involved in blocking g1 exit , but does not interact with inactive hyperphosphorylated forms of prb [ mittnacht et al . ,
presumably , the frugality of targeting only those cellular proteins actively engaged in some activity preserves adequate levels of unbound e1a to serve all necessary cellular targets .
however , the exact role of the interaction of the e1a protein with the tr is not clear .  
inspection of the human adenovirus 5 genome failed to identify any consensus direct repeat tres , but a number of consensus half sites are present .  
it remains to be determined if the tr can function through these half sites and whether the e1a proteins can influence any such activity , but it is tempting to speculate that they may play a role in controlling viral transcription and or replication in some fashion . given similarities between nuclear hormone receptors , it is also possible that e1a could engage in functionally important interactions with corepressor binding domains of other members of this family of transcription factors . nevertheless , there is precedent for a role of thyroid hormone in regulating viral life cycle , as simian virus 40 , human immunodeficiency virus type 1 and herpes simplex virus all contain functional tres that control viral gene transcription [ desai - yajnik et al . , 1995 ; desvergne and favez , 1997 ; park et al . , 1993 ; zuo et al . ,
these studies on the viral e1a protein also culminated in the novel observation that a nuclear receptor corepressor splice variant ( n - cori ) or a c - terminal fragment of n - cor ( n - corc ) also act as htr coactivators that bind in the repressor mode [ meng et al .
both n - cori and n - corc lack the autonomous n - terminal repression domain found in the well characterized full length form of n - cor .   in the absence of the n - terminal domain , a paradoxical constitutive coactivation function
can be observed which is dependent upon binding to htr in a corepressor mode [ meng et al . ,
n - cori / n - corc or e1a thus act as novel constitutive coactivators ( ccs ) through the interaction of their cbms with tr in the absence of th [ meng et al .
although , this mechanism appears entirely different from that of th dependent coactivators ( dcs ) , such as grip1 or src1 [ anafi et al . , 2000 ;
2003 ] , both types of coactivators nevertheless enhance transcription of their target genes . to further explore the mechanisms by which n - cori / n - corc function as activators ,
we constructed deletion mutants and determined that cbm1 is much more important than cbm2 and cbm3 for coactivation ( figure 1 ) . if cbm1 was deleted , more than 90% of activity was lost .
we also determined that cbm1 contains an intrinsic activation function using yeast one hybrid analysis ( data not shown ) .  
although full - length n - cor ( fl - n - cor ) acts as a tr corepressor , n - cori / n - corc function as coactivators that bind and activate unliganded tr in a yeast coexpression system .  
this likely occurs because these splice variants of n - cor lack the intrinsic n - cor repressor domain and harbor a hitherto unrecognized coactivator function that lies in the vicinity of cbm1 .
when a p160 coactivator is coexpressed in a yeast model system [ anafi et al . , 2000
1997 ] or is endogenously present in a mammalian cell , th induces hormone dependent coactivation ( dc ; figure 2 , left panel ) .  
in contrast , when a p160 coactivator is either not present or expressed at a relatively low level , th induces a hormone dependent repression ( i.e. negative regulation ) on the constitutive unliganded coactivation of n - cori ( cc ; figure 2 , right panel ) .
it must be acknowledged that experimental evidence for the physiological relevance of ligand independent activation by n - cori in mammalian cells is lacking .
however , splice variants devoid of n - terminal repressor domains have been isolated in mammalian cells for n - cori [ hollenberg et al . ,
1996 ] as well as s - smrt [ chen and evans , 1995 ; ordentlich et al . , 1999 ] and trac-1 [ sande and privalsky , 1996 ] .
moreover , these splice variants have been observed to not only be devoid of repressor function but may also have a dominant - negative inhibitory effect on corepressor function [ chen and evans , 1995 ; hollenberg et al . , 1996 ; sande and privalsky , 1996 ] and
thus , it remains a possibility that ratio differences in the cellular context of corepressor fl compared to their splice variants may result in either an overall anti - corepressor or perhaps a predominant coactivator influence on tr regulated genes .
intriguingly , there is increasing recognition that splice variants of n - cor and smrt corepressors may be adapted and tailored by alternative mrna splicing to different cells and to different developmental stages as a mechanism for regulating metazoan gene expression ( see [ goodson et al . , 2005a ] and references therein ) .
moreover , differences in the expression of corepressors in different tissues and at various times of development suggest that organisms may adapt to their corepressor repertoire for distinct biological purposes [ jepsen et al . ,
2000 ] . since a number of alternatively spliced variants have been shown to differ in their abundance at different times of development or in different tissues [ goodson et al .
2005 ] , further studies will be required to fully understand the biological properties of such sequences .
it is likely that modules within n - cor and smrt regulate the repression or activation of target genes by recruiting domain specific transcriptional regulators ( see [ goodson et al . , 2005a ] and references therein ) .
although the characterization of such regulators is still in its infancy , alternative splicing events could represent a mechanism by which cells can modulate varying degrees of corepression or coactivation of target genes .
it is possible that there are other mechanisms which could alter the ratio of full - length corepressors and their splice variants in mammalian cells .
fl - n - cor is targeted for proteasomal degradation by interaction with the msiah2 ubiquitin ligase , which binds the n - terminal 160 amino acid residues [ zhang et al . ,
is absent in n - cori , msiah2 should preferentially degrade fl - n - cor .  
this could alter the ratio of fl - n - cor to n - cori and potentially influence gene expression .  
msiah2 expression is known to be cell - type specific [ zhang et al . ,
interestingly , estrogen up - regulates msiah2 expression leading to the subsequent degradation of fl - n - cor [ frasor et al . , 2005 ] , suggesting the presence of a complex feedback pathway that could come into play under certain conditions .
future studies should focus on the identification and characterization of genes essential for cc or dc mediated gene activation by nrs .
it is likely that some of these genes will play a role in regulating cor function , whether by affecting their transcription , splicing , degradation or post - translational modifications in normal , pathogenically infected or disease stage cellular contexts [ perissi and rosenfeld , 2005 ] .
left side : a schematic depiction of the portions of n - corc used in this study , which were fused to the gal4-dna binding domain .
the amino acid residues present in each fragment are as indicated , as are the positions of the cbms .   
right side : -gal assays were performed with a yeast strain containing a -galactosidase reporter gene regulated by single copy of the chicken lysozyme ( f2 ) tre and expressing htr1 , the indicated portions of n - corc or empty vector .
cultures were treated with either vehicle ( grey bars ) or 10 m triac ( black bars ) .
assay conditions as described previously [ meng et al . , 2005 ; walfish et al . ,
left side : the transcriptional response of fl - n - cor and a p160 coactivator in the absence and presence of th .  
right side : the constitutive coactivation ( cc ) of a natural splice variant n - cori in the absence and presence of th .
the functional consequences of the interaction of transcriptional coregulators with the human thyroid hormone receptor ( tr ) in mammalian cells are complex . 
 we have used the yeast , saccharomyces cerevisiae , which lack endogenous nuclear receptors ( nrs ) and nr coregulators , as a model to decipher mechanisms regulating transcriptional activation by tr . in effect 
 , this system allows the reconstitution of tr mediated transcription complexes by the expression of specific combinations of mammalian proteins in yeast . in this yeast system , 
 human adenovirus 5 early region 1a ( e1a ) , a natural n - cor splice variant ( n - cori ) or an artificial n - cor truncation ( n - corc ) coactivate unliganded trs and these effects are inhibited by thyroid hormone ( th ) . 
 e1a contains a short peptide sequence that resembles known corepressor - nr interaction motifs ( cornr box motif , cbm ) , and this motif is required for tr binding and coactivation . 
 n - cori and n - corc contain three cbms , but only the c - terminal cbm1 is critical for coactivation . 
 these observations in a yeast model system suggest that e1a and n - cori are naturally occurring tr coactivators that bind in the typical corepressor mode . 
 these findings also raise the possibility that alternative splicing events which form corepressor proteins containing only c - terminal cbm motifs could represent a novel mechanism in mammalian cells for regulating constitutive transcriptional activation by trs .