Disease relevance of NCOA2

• A further case of acute myelomonocytic leukemia with inv(8) chromosomal rearrangement and MOZ-NCOA2 gene fusion [1].
• The expression levels of ER-alpha, TIF2, and CBP were significantly higher in the intraductal carcinomas than those in the normal mammary glands [2].
• AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy [3].
• To explain how these differences in transactivation might occur, we have examined the interaction of ERbeta with these EREs and monitored recruitment of the coactivators amplified in breast cancer (AIB1) and transcription intermediary factor 2 (TIF2) [4].
• Thus, HNF4 is involved in the regulation of glucose homeostasis at several levels and along with the SRC-1, GRIP1, and p300 may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus [5].

Psychiatry related information on NCOA2

• Moreover, neurones and glial cells do not over-express phosphorylated TIF 2 alpha in CJD [6].
• Hand function was evaluated by measuring subjects' grip and pinch strength, range of motion, edema, and sensation and with the Grip Function Test and self-assessment scale [7].

High impact information on NCOA2

• Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2 [8].
• Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain (LBD) of the thyroid hormone receptor that interacts with an LxxLL motif-containing alpha-helix from GRIP1, a coactivator [9].
• Our study demonstrates that ERalpha is a TNFalpha-induced coactivator that becomes a repressor in the presence of estradiol by recruiting GRIP1 [10].
• LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2 [11].
• TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC-1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators [12].

Chemical compound and disease context of NCOA2

• Our experiments also showed that one member of the p160 family of steroid receptor coactivators, steroid receptor coactivator (SRC)-1, but not glucocorticoid receptor interacting protein 1 (GRIP1) or amplified in breast cancer 1 (AIB1), also functioned in gene transactivation in response to leptin treatment [13].

Biological context of NCOA2

• As seen in the previous cases, the inv(8)(p11q13) molecular characterization showed that the alteration results in a MOZ-NCOA2 gene fusion [1].
• In a transient expression assay, a combination of p72/p68 with SRA and one TIF2 brought an ultimate synergism to the estrogen-induced transactivation of hER alpha [14].
• The reciprocal TIF2-MOZ fusion gene is not expressed, perhaps as a result of a deletion near the chromosome 8 centromere [15].
• Here we have shown that MOZ-TIF2 associates with the RARbeta2 promoter in vivo, resulting in altered recruitment of CBP/p300, aberrant histone modification, and down-regulation of the RARbeta2 gene [16].
• This likely reflects a direct interaction between these proteins because mutation of a conserved residue within the major coactivator binding site on AR (K720A) inhibits AR-dependent dissociation of GRIP-1 from foci [17].

Anatomical context of NCOA2

• The CBP-binding domain is also required for the ability of MOZ-TIF2 to extend the proliferative potential of murine bone marrow lineage-negative cells in vitro [18].
• Compared with both fertile and infertile controls, PCOS women exhibited elevated levels of AIB1 and transcriptional intermediary factor-2 expression in both epithelial and stromal cells [19].
• The enhanced ability of ERbeta (over ERalpha) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ERbeta to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIF2 [20].
• Compared with the interaction of VDR with RXR or GRIP-1, the differentiation dose-response most closely correlated to the ligand-dependent recruitment of the DRIP coactivator complex to VDR and to the ability of the receptor to activate transcription in a cell-free system [21].
• SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4 [5].

Associations of NCOA2 with chemical compounds

• Estrogen induced co-localization of p72 with hER alpha and TIF2 in the nucleus [14].
• The expression of SRC-1 and TIF2 is significantly related to progesterone but not to estrogen receptor expression [22].
• These results indicate that residue Q902 is involved in TIF2 and NH2/COOH interaction and that the Q to K mutation results in a mild impairment of AR function, which can explain the partial AIS phenotype of the patient [23].
• An antiestrogen, 4-hydroxytamoxifen, significantly inhibited E2-mediated transactivation and interaction between hER alpha and TIF2 through hER alpha binding (p < 0.05) [24].
• TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors [12].

Physical interactions of NCOA2

• We observe that TIF2 is capable of interacting simultaneously with both the isolated N- and C-terminus of ER alpha in transfected mammalian cells and in vitro, indicating that TIF2 can bridge both receptor domains [25].
• For the Glu897 substitutions, the decrease in ligand-dependent transactivation could partially be reversed by overexpression of GRIP1 (GR-interacting protein 1) or CBP, putative coactivators for AR [26].
• We propose that TIF2 provides a nuclear compartment that allows the assembly of multi-protein complexes required for GR-mediated gene activation [27].
• SHP specifically targets the ligand-regulated activation domain AF-2 and competes for binding of coactivators such as TIF2 [28].

Other interactions of NCOA2

• The MOZ-TIF2 fusion is one of a new family of chromosomal rearrangements that associate HAT activity, transcriptional coactivation, and acute leukemia [15].
• ERbeta and GRIP1/TIF2 are shown to interact in vitro in a ligand-dependent manner and thus may form functional transcription complexes in NSCLC cells [29].
• We therefore developed antisense oligodeoxynucleotides (asODNs) to SRA, SRC-1, and TIF2 mRNAs, which rapidly and specifically reduced the expression of each of these coactivators [30].
• Significantly, the effects of TIF2 and SMRT were mutually antagonistic [31].
• In contrast, seven normal brain specimens were positive for TIF2 and SRC-1 but negative for AIB1 [22].

Analytical, diagnostic and therapeutic context of NCOA2

• Co-immunoprecipitation experiments demonstrate that PPAR alpha and GRIP1/TIF2 physically interact in vivo in human liver [32].
• Using mammalian two-hybrid assays, hAR amino/carboxyl (N/C)-terminal interactions of the mutant receptors were analyzed in the presence and absence of the hAR coactivator transcription intermediary factor 2 (TIF2) [33].
• Moreover, surface plasmon resonance analysis revealed reduced interaction of the V320G ERbeta variant with the NR box I and II modules of TIF2 [34].
• Among co-activators such as SRC-1, TIF-2, and p300, PPARdelta had more strong binding with SRC-1 in an ELISA system [35].
• Rearrangements were detected by Southern blotting with a TIF2 probe that was close to the breakpoint in the original inv(8) case and with a MOZ probe corresponding to the breakpoint cluster region in the t(8;16) (p11;p13) [36].

References