Table 1.

Mediator modules, subunits and interacting TFs and Pol II CTD

Mediator Module	Subunit	Interacting TF	Reference(s)
Head	MED22	Gcn4	[109]
Head	MED17	VP16	[88]
Head	MED17	PGC-1α	[104]
Head	MED17	p53	[27]
Middle	MED1	p53	[27]
Middle	MED1	C/EBPβ	[103]
Middle	MED1	PGC-1α	[104]
Middle	MED1	ERa; ERβ	[105]
Middle	MED1	RAR	[110]
Middle	MED1	HNF-4	[111]
Middle	MED1	TR	[112]
Middle	MED1	Pit-1, GATA-1, GATA-2	[113]
Middle	MED1	PPARγ	[114]
Middle	MED1	GR	[85,86]
Middle	MED1	GABP	[115]
Middle	MED12	RTA	[116]
Middle	MED12	β-catenin	[117]
Middle	MED12	Gli3	[118]
Middle	MED12	Sox9	[119]
Middle	MED21	Tup1	[120]
Tail	MED2	Gcn4	[121,122]
Tail	MED3	Gcn4	[121]
Tail	MED14	HNF-4	[111]
Tail	MED14	GR	[85]
Tail	MED14	SREBP1a	[123]
Tail	MED15	VP16, Gal4	[89]
Tail	MED15	GR, NHP49	[87]
Tail	MED15	Smad2-Smad4	[124]
Tail	MED15	Gcn4	[89,109,121]
Tail	MED15	SREBP1a	[125]
Tail	MED16	PGC-1α	[104]
Tail	MED16	Gcn4	[109]
Tail	MED23	E1A, Elf3	[126]
Tail	MED23	C/EBPβ	[127]
Tail	MED25	VP16	[89]
Tail	MED25	RAR	[110]

Mediator is a huge multi-protein complex (26 subunits in the human [79]). It is the primary regulator of the PEC, which includes TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, Mediator and Pol II [27,79]. Mediator is divided into Head, Middle and Tail modules. The interactions and functions of some subunits have been partly elucidated [24–27,79]. The Table lists some of the known TF AD interactions [24]. Because only scant structural data are available, we have not distinguished between yeast and human. The CDK8 submodule triggers Mediator conformational change [79], MED5 has acetyltransferase activity, and Tail MED14 was shown recently to bind the N-terminal domain of PPARγ [26]. The partial list in this Table illustrates that a TF can bind multiple Mediator subunits even belonging to different modules (e.g. p53, GCN4); however, a TF can also require different subunits, as in p53 activation of p21 by Nutlin which does not require CDK8, whereas UV light C does [60]. Such cases could relate to communication pathways. Secondly, TFs do not necessarily require the same subunits. For example, while MED1 is not required for PPARγ [26], it is required by, for example, C/EBPβ [103], PGC-1α [104] and ERα [105]. Yeast and human subunit interaction maps have been constructed [35,40,41]. The Pol II CTD has up to 52 heptapeptide repeats (YSPTSPS) [106]. Ser⁵ and Ser⁷ are phosphorylated by CDK7 (TFIIH) which is recruited (with TFIIB) by Mediator–Pol II complex before transcription initiation [107]. Ser² phosphorylation by CDK9 is required for elongation. Ser⁵ phosphorylation is required for initiation of transcription elongation. Submodule CDK8 phosphorylates CDK7. Key mechanistic questions relate to how TF–Mediator binding activates Pol II and how this relates to the CTD phosphorylation requirement. C/EBPβ, CCAAT/enhancer-binding protein β; E1A, early region 1A; ER, oestrogen receptor; GABP, GA-binding protein; Gli3, GLI family zinc finger 3; GR, glucocorticoid receptor; HNF-4, hepatocyte nuclear factor 4; PGC-1α, PPARγ co-activator-1α; RTA, replication and transcription activator; Sox9, SRY (sex-determining region Y)-box 9; RAR, retinoic acid receptor; TR, thyroid hormone receptor.