Disease relevance of TTF2

• Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15) [1].
• Hitherto, two mutations in the human thyroid transcription factor 2 (TTF-2) gene have been described in unrelated cases of CH with cleft palate, spiky hair, variable choanal atresia, and complete thyroid agenesis [2].
• Recombinant human factor 2 was produced in a baculovirus expression system, purified, and characterized [3].
• Germline mutations in thyroid transcription factor 2 (TTF2) cause thyroid agenesis, spiky hair, and cleft palate, indicating thyroidal and extrathyroidal expression [4].
• The host protein required for in vitro replication of poliovirus is a protein kinase that phosphorylates eukaryotic initiation factor-2 [5].

Psychiatry related information on TTF2

• Prostaglandins F2 alpha and thromboxane B2, additional products of the cyclooxygenase pathway of arachidonic acid metabolism, were also elevated in dementia, but leukotriene C4, a product of the lipoxygenase pathway was not [6].
• When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables [7].
• Factor 2 (mutism, stereotypy, catalepsy, automatic obedience) corresponded to the classical description of catatonia, was associated with a research diagnosis of mania, and tended (p less than 0.10) to predict a favorable treatment response [8].
• Both pain report and psychological distress were found to be related to use of strategies within factor 2 (Helplessness), the number of different drugs patients used, and the time they had experienced phantom limb pain [9].
• Sequential interactions of fibroblast growth factor-2, brain-derived neurotrophic factor, neurotrophin-3, and their receptors define critical periods in the development of cochlear ganglion cells [10].

High impact information on TTF2

• EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome [11].
• Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia [12].
• Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast [13].
• Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2 [14].
• Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling [15].

Chemical compound and disease context of TTF2

• Both virus-associated RNA and 2-aminopurine presumably exert their effect by alteration of the functional level of eucaryotic initiation factor-2 [16].
• Treatment of MDA-MB-231 and MDA-MB-468 breast cancer cells with phosphoinositide-specific phospholipase-C abrogated the mitogenic response to two heparin-binding growth factors, heparin-binding epidermal growth factor-like growth factor and fibroblast growth factor 2 [17].
• Our results show clearly that murine Lewis lung carcinoma cells overexpressing placenta growth factor-2, an Flt-1-specific ligand, grew in wild-type mice much faster than in Flt-1 tyrosine kinase domain-deficient mice [18].
• Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 receptor binding in breast carcinomas [19].
• Fibroblast growth factor-2 antagonist activity and angiostatic capacity of sulfated Escherichia coli K5 polysaccharide derivatives [20].

Biological context of TTF2

• Consistent with a role in termination of all transcription, TTF2 is the only ATP-dependent termination activity associated with Pol II transcription elongation complexes, is largely unaffected by template position, and is impervious to the phosphorylation state of the polymerase [21].
• Cells in which TTF2 levels are knocked down showed dramatic retention of Ser2 phosphorylated Pol II on mitotic chromosomes and an increase in chromosome segregation defects [21].
• We find that TTF2 levels rise in the cytoplasm in S and G2 and at the onset of mitosis TTF2 translocates into the nucleus [21].
• Rescue of the TTF2 knockdown phenotype with an siRNA-resistant replacement vector [22].
• Transient transfection experiments demonstrate that endogenous TTF2 and GFP-tagged wild-type TTF2 are both sensitive to the siRNA, but GFP-tagged TTF2 encoded by the cDNA containing mismatches is abundantly expressed in the presence of TTF2-siRNA [22].

Anatomical context of TTF2

• PCR products of cDNA clones obtained by a subtraction PCR method in TTF-2 expressing cell lines were screened with labeled cDNA by microarray analysis [23].
• We also found that a truncated hLodestar/HuF2 polypeptide that overlaps with the CDC5L-binding region can inhibit pre-mRNA splicing by disrupting spliceosome assembly [24].
• The exceptions were testis and skin, in which nuclear TTF2 immunoreactivity was present in the seminiferous tubules and cells in the follicular outer root sheath, respectively [4].
• Biological roles of fibroblast growth factor-2 [25].
• B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes [26].

Associations of TTF2 with chemical compounds

• Results: The index case is homozygous for an arginine to cysteine mutation (R102C) of a highly conserved residue within the forkhead, DNA binding domain of TTF-2 [2].
• Human transcription release factor 2 dissociates RNA polymerases I and II stalled at a cyclobutane thymine dimer [27].
• Rabbits were immunized and the resulting TTF2 polyclonal titrated on formalin-fixed, paraffin-embedded sections of thyroid [4].
• Dendrimer glucosamine 6-sulfate blocked fibroblast growth factor-2 mediated endothelial cell proliferation and neoangiogenesis in human Matrigel and placental angiogenesis assays [28].
• Interleukin 1 regulates heparin-binding growth factor 2 gene expression in vascular smooth muscle cells [29].

Physical interactions of TTF2

• hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing [24].
• HDAC9 and HDAC9a also repress myocyte enhancer-binding factor 2-mediated transcription [30].
• Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2 [31].
• Laminin alpha5 chain metastasis- and angiogenesis-inhibiting peptide blocks fibroblast growth factor 2 activity by binding to the heparan sulfate chains of CD44 [32].
• Direct interaction of Ca2+/calmodulin inhibits histone deacetylase 5 repressor core binding to myocyte enhancer factor 2 [33].

Enzymatic interactions of TTF2

• The interferon-inducible double-stranded (ds) RNA-activated protein kinase (p68 kinase) is a physiologically important enzyme that regulates the rate of cellular and viral protein synthesis by phosphorylating and thereby inactivating the peptide chain initiation factor 2 [34].
• Casein kinase-2 phosphorylates serine-2 in the beta-subunit of initiation factor-2 [35].

Co-localisations of TTF2

• Cyclin L2 interacted with splicing factor 2 in vitro and was co-localized with the splicing factor SC35 in the nuclear speckle compartment [36].

Regulatory relationships of TTF2

• In this paper, we demonstrate that TTF-2 is able to inhibit the activity of the thyroid-specific transcription factors TTF-1 and Pax-8 only on certain promoters [37].
• METH proteins suppressed fibroblast growth factor-2-induced vascularization in the cornea pocket assay and inhibited vascular endothelial growth factor-induced angiogenesis in the chorioallantoic membrane assay [38].
• Myocyte-specific enhancer binding factor 2C (MEF2C) activates transcription by binding to the myocyte-specific enhancer binding factor 2 (MEF2) regulatory element and has been shown previously to be expressed in muscle and in the brain [39].
• Fibroblast growth factor-2 suppresses oridonin-induced l929 apoptosis through extracellular signal-regulated kinase-dependent and phosphatidylinositol 3-kinase-independent pathway [40].
• Tumour suppressor p53 inhibits human fibroblast growth factor 2 expression by a post-transcriptional mechanism [41].

Other interactions of TTF2

• We examined the role of human TTF2, an RNA polymerase (Pol) I and II termination factor, in mitotic repression of transcription elongation [21].
• We now show that follicular TG, 27S > 19S > 12S, counter-regulates TSH-increased thyroid-specific gene transcription by suppressing the expression of the TTF-1, TTF-2, and Pax-8 genes [42].
• Genes associated with thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital hypothyroidism, and Gsalpha and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8), associated with different complex syndromes that include congenital hypothyroidism [43].
• We suggest that TTF-2 is able to interfere with a specific cofactor required for TTF-1 and Pax-8 activity [37].
• There were continuous increases in mRNAs for cartilage matrix (proteoglycans and COL2, -9, -10, and -11), receptors [fibroblast growth factor 2 (FGFR2) and parathyroid hormone-related peptide receptor (PTHrP-R)], and transcription factors (SOX5, -6, and -9) as demonstrated by histochemical and microarray assays [44].

Analytical, diagnostic and therapeutic context of TTF2

• We isolated 17 genes up-regulated by TTF-2, which were subsequently confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) [23].
• This hypothesis was addressed in the context of muscle regeneration by transplanting satellite cells to muscle laceration sites on a delivery vehicle releasing factors that induce cell activation and migration (hepatocyte growth factor and fibroblast growth factor 2) or transplantation on materials lacking factor release [45].
• Using blocked design functional MRI and statistical parametric mapping, we investigated the impact of remoteness (factor 1: recent, remote) and emotional valence (factor 2: positive, negative) on the neural correlates of autobiographical memory retrieval [46].
• Interactions of eukaryotic 5-dimethylaminonaphthalene-1-sulfonyl-initiation factor 2 (eIF-2) from rabbit reticulocytes and the guanine nucleotide exchange factor ( GEF ), Met-tRNAf, GTP, and GDP were monitored by changes in fluorescence anisotropy and radioactive filtration assays [47].
• UV cross-linking assays followed by immunoprecipitation with anti-SR protein monoclonal antibodies showed that ESEwt, but not mutated ESE RNA, was able to bind both alternative splicing factor/splicing factor 2 and SC35 [48].

References