ライフサイエンスコーパス: TRAP220

1 rs that are functionally redundant with MED1/TRAP220.

2 and (at least in part) the LXXLL domains of TRAP220.

3 from nuclear receptor coactivators SRC1 and TRAP220.

4 g to flERE.E2-ER than an NR box peptide from TRAP220.

5 nd no change in TMF1/ARA160, ARA54, SRC1, or TRAP220.

6 s can be restored by expression of exogenous TRAP220.

7 sts reveal that these interactions depend on TRAP220, a TRAP/Mediator subunit previously shown to int

8 These data indicate that TRAP220 acts, via the TRAP complex, as a PPAR gamma(2)-s

9 TRAP220 also interacts with other nuclear receptors [vit

10 on of two integral Mediator components, MED1/TRAP220 and MED17, in prostate cancer cells.

11 there is a conditional requirement for MED1/TRAP220 and that a direct interaction between PPARgamma

12 Both TRAP220 and TRAP100 contain LXXLL domains found in other

13 nuclear receptor recognition motifs on MED1/TRAP220 and, furthermore, we show that the intact LXXLL

14 r, through the PPARgamma-interacting subunit TRAP220, and stimulates TRAP/Mediator-dependent function

15 eceptor function that is restored by ectopic TRAP220 but no defect in activation by Gal4-RARalpha/RXR

16 esults, we suggest that a single molecule of TRAP220 can interact with both subunits of a DNA-bound N

17 The 220-kDa subunit of the complex (TRAP220) can contact the ligand-binding domain of AR in

18 We show that Trap220(-)(/)(-) cells possess a TRAP/Mediator complex t

19 An analysis of endogenous genes in Med1/Trap220-/- cells has confirmed a variable MED1/TRAP220 r

20 or RXR-VDR heterodimers bound to DNA and for TRAP220 coactivator function.

21 The TRAP220 component of the TRAP/SMCC complex, a mammalian

22 Importantly, this MED1/TRAP220-containing holoenzyme supports both basal- and a

23 A MED1/TRAP220-containing Mediator complex constitutively occup

24 e an activator-selective recruitment of MED1/TRAP220-containing versus MED1/TRAP220-deficient TRAP/Me

25 r complex and that both LXXLL motifs of MED1/TRAP220 contribute to its binding to GR.

26 tment of MED1/TRAP220-containing versus MED1/TRAP220-deficient TRAP/Mediator complexes to estrogen re

27 nteracts with PPAR gamma(2) in a ligand- and TRAP220-dependent manner.

28 the TRAP/Mediator complex and, further, that TRAP220-dependent TR function in transfected cells requi

29 tivated receptor (PPAR)-binding protein (PBP/TRAP220/DRIP205/Med1) in the mouse results in embryonic

30 cks entirely MED1/TRAP220, we show that MED1/TRAP220 enhances GR-mediated transcription from an MMTV

31 20(-)(/)(-) mice and by the observation that Trap220(-)(/)(-) fibroblasts (isolated before embryonic

32 Here we show that Trap220(-/-) fibroblasts are refractory to PPAR gamma(2)

33 Studies with extracts from TRAP220(-/-) fibroblasts reveal that these interactions

34 ch to understand the basis of specificity in TRAP220 function.

35 Disruption of the PBP/TRAP220 gene results in embryonic lethality around embry

36 Ablation of the murine Trap220 gene revealed that null mutants die during an ea

37 TRAP220 has been reported to show ligand-enhanced intera

38 ncers we examined, thus suggesting that MED1/TRAP220 hyperactivity may have implications in prostate

39 vidence in support of a critical role of PBP/TRAP220 in liver regeneration, induction of hepatotoxici

40 Further indicative of a direct role for TRAP220 in PPAR gamma(2) function via the TRAP complex,

41 ish a direct role for TRAP/Mediator, through TRAP220, in ER function.

42 motifs of the coactivators GRIP1 and SRC1 or TRAP220 interacted predominantly with the TR.retinoid X

43 by largely independent PPARgamma, p300, and TRAP220 interaction domains in PGC-1alpha, whereas p300

44 domain of AR in vitro, possibly implicating TRAP220 involvement in targeting AR to the holocomplex.

45 Moreover, in undifferentiated MEFs, MED1/TRAP220 is dispensable both for PPARgamma-mediated targe

46 These results indicate that TRAP220 is essential for a wide range of physiological p

47 The critical but selective function of TRAP220 is evidenced by the embryonic lethal phenotype o

48 P220 mutants revealed that the N terminus of TRAP220 is necessary and sufficient for stable associati

49 between PPARgamma and Mediator through MED1/TRAP220 is not essential either for PPARgamma-stimulated

50 Furthermore, we show that MED1/TRAP220 is overexpressed in both AR-positive and -negati

51 romatin immunoprecipitation assays show that TRAP220 is recruited to the androgen-responsive prostate

52 Finally, RNAi studies show that MED1/TRAP220 is required for ER-mediated transcription and es

53 nteractions with distinct subunits, and MED1/TRAP220 is the main subunit target for various nuclear r

54 A single subunit, TRAP220, is thought to target the entire complex to a li

55 reporter gene and that mutations in the MED1/TRAP220 LXXLL motifs reduce, but do not eliminate, GR-de

56 ERK phosphorylation of ectopic TRAP220/Med1 also triggered shuttling into the nucleolus

57 urora-A gene via direct interactions between TRAP220/MED1 and the Ets-related transcription factor GA

58 whose expression is affected by the loss of TRAP220/MED1 by RNA interference.

59 xpression and that ectopic overexpression of TRAP220/MED1 coactivates transcription from the Aurora-A

60 In general, we found that TRAP220/MED1 expression is required for high basal level

61 tion is a regulatory mechanism that controls TRAP220/Med1 expression levels and modulates its functio

62 Ablation of the Trap220/Med1 gene in mice impairs embryonic cell growth,

63 Furthermore, ERK phosphorylates TRAP220/Med1 in a cell cycle-dependent manner, resulting

64 tly increases the stability and half-life of TRAP220/Med1 in vivo and correlates with increased thyro

65 We demonstrate that ERK phosphorylates TRAP220/Med1 in vivo at two specific sites: threonine 10

66 TRAP220/Med1 is a key component of TRAP/Mediator that ta

67 We show here that human TRAP220/Med1 is a specific substrate for extracellular s

68 TRAP220/MED1 is a variably associated subunit of the com

69 conclude that transcription coactivator PBP/TRAP220/MED1 is involved in the regulation of hepatic CA

70 Taken together, these findings suggest that TRAP220/MED1 plays a novel coregulatory role in facilita

71 lly, we observed that ERK phosphorylation of TRAP220/Med1 stimulates its intrinsic transcriptional co

72 eolus, thus suggesting that ERK may regulate TRAP220/Med1 subnuclear localization.

73 ators, including p160 family members and the TRAP220/MED1 subunit of the Mediator co-activator, to pr

74 romatin immunoprecipitation assays show that TRAP220/MED1-containing TRAP/Mediator complexes directly

75 idenced by the embryonic lethal phenotype of Trap220(-)(/)(-) mice and by the observation that Trap22

76 Consistent with these results, TRAP220 moderately stimulates human TRalpha-mediated tra

77 Furthermore, using a Med1/Trap220-/- mouse embryonic fibroblast (MEF) line that la

78 Transfection studies using TRAP220 mutants revealed that the N terminus of TRAP220

79 All these events are abolished in Med1/Trap220 null cells, indicating a key role for TRAP/Media

80 emarkably, the current study shows that MED1/TRAP220 only exists in a TRAP/Mediator subpopulation (le

81 for the first time that loss of either MED1/TRAP220 or MED17 in prostate cancer cells significantly

82 gamma or the PPARgamma-binding protein (PBP, TRAP220, or DRIP205).

83 A single DRIP subunit, DRIP205 (TRAP220, PBP), binds directly to PPARgamma.

84 These studies indicate that TRAP220 plays a major role in anchoring other TRAPs to T

85 MED1/TRAP220 plays a particularly important role in androgen

86 that Mediator, at least in part through MED1/TRAP220, plays a coregulatory role in ligand-dependent G

87 the TRalpha-TRAP complex and, further, that TRAP220 (possibly along with other TRAPs) may be a globa

88 The isolated MED1/TRAP220 protein previously was shown to interact with gl

89 ap220-/- cells has confirmed a variable MED1/TRAP220 requirement for different GR target genes.

90 tion domains in PGC-1alpha, whereas p300 and TRAP220 show ligand-dependent interactions with a common

91 However, only TRAP220 shows a direct ligand-dependent interaction with

92 n that the nuclear receptor-interacting MED1/TRAP220 subunit of Mediator is required for peroxisome p

93 The MED1/TRAP220 subunit of the Mediator plays a key role in faci

94 ion 2 (AF-2)-dependent interactions with the TRAP220 subunit of TRAP/SMCC/Mediator and secondary (AF-

95 y with several nuclear receptors through the TRAP220 subunit, and with diverse activators through oth

96 t interactions of nuclear receptors with the TRAP220 subunit, p53 and VP16 activation domains interac

97 yroid hormone receptor (TR) that targets the TRAP220 subunit.

98 ingly, a conserved N-terminal region of MED1/TRAP220 that lacks the LXXLL motifs but gets incorporate

99 ivator role, transient overexpression of the TRAP220, TRAP170, and TRAP100 subunits enhanced ligand-d

100 NUT2), and, significantly, some components (TRAP220, TRAP170/hRGR1, and TRAP100) of a human thyroid

101 al coactivating proteins such as SRC1, SRC2, TRAP220, TRBP, p300, and ARA70; and those in coregulator

102 broblast (MEF) line that lacks entirely MED1/TRAP220, we show that MED1/TRAP220 enhances GR-mediated

103 2 are required for an optimal association of TRAP220 with RXR-TR or RXR-VDR heterodimers bound to DNA

104 However, the functional role of MED1/TRAP220, within the context of the entire Mediator, is n