Disease relevance of TERF1

• Here we investigated the expressions of the mRNAs encoded by the TERF1 and TERF2 genes using in situ hybridization in surgically resected specimens [28 AAHs (11 lesions were interpreted as low-grade AAH, and 17 were interpreted as high-grade AAH) and 40 peripherally located bronchioloalveolar carcinoma (BAC) [1].
• SNP and haplotype analyses in acquired AA patients suggested that one variant allele, in intron 9 of TERF1, and haplotype could be associated with increased risk for aplastic anemia (OR 1.59, 95% confidence interval 1.06-2.39, p = 0.033) [2].
• The transcriptional expression of these genes, TRF1 protein, and telomere length was examined in 9 normal livers, 14 chronic hepatitis, 24 liver cirrhosis, 5 large regenerative nodules, 14 low-grade dysplastic nodules (DNs), 7 high-grade DNs, 10 DNs with hepatocellular carcinoma (HCC) foci, and 31 HCCs [3].
• Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung [1].
• Telomerase reverse transcriptase and telomeric-repeat binding factor protein 1 as regulators of telomerase activity in pancreatic cancer cells [4].

Psychiatry related information on TERF1

• The constellation of normal quantitative but abnormal kinetic LRF and TRF responses supports the hypothesis that the endocrine changes seen in anorexia nervosa are consistent with hypothalamic dysfunction [5].
• For the assessment of behaviour problems the Child Behavior Checklist (CBCL), Teacher Self Report (TRF), and Youth Self Report (YSR) were filled out by parents, teachers, and children, respectively [6].
• Children were screened for ADHD and other problems, using the C-DISC, CBLC, TRF and the Social Adjustment Inventory [7].

High impact information on TERF1

• TRF1 itself can be inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its interacting partner tankyrase 1, which abolishes its DNA binding activity in vitro and removes the TRF1 complex from telomeres in vivo [8].
• These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length [8].
• Telomere length in humans is partly controlled by a feedback mechanism in which telomere elongation by telomerase is limited by the accumulation of the TRF1 complex at chromosome ends [8].
• In human cells, telomere protection depends on the TTAGGG repeat binding factor, TRF2 (refs 1-4), which has been proposed to remodel telomeres into large duplex loops (t-loops) [9].
• TIN2 interacted with TRF1 in vitro and in cells, and co-localized with TRF1 in nuclei and metaphase chromosomes [10].

Chemical compound and disease context of TERF1

• Results showed that treatment of human gastric cancer MGC-803 cells with arsenic trioxide could cause up-regulation of telomeric repeat binding factor TRF1 and TRF2 mRNA and protein levels, and induced G2/M phase arrest and cell apoptosis [11].
• Biochemical analysis indicated that TERF1 binds to the GCC box (an element responsive to ethylene) and to the dehydration responsive element, which is responsive to the osmoticum [12].
• Serum levels of thyroid-stimulating hormone (TSH), before and after thyrotropin-releasing factor (TRF) administration, were in the range generally considered to be indicative of primary, rather than secondary, hypothyroidism [13].
• Plasma ACTH and cortisol responses to TRF, vasopressin or hypoglycemia in cushing's disease and nelson's syndrome [14].
• If NIDD subjects are grouped according to their Alb/Cr ratio into normal albuminuria (Group A, Alb/Cr less than 2.5 mg/mmol), microalbuminuria (Group B, Alb/Cr 2.5-26.8 mg/mmol), and macroalbuminuria (Group C, Alb/Cr greater than 26.8 mg/mmol), the TRF/Cr ratios in all three groups exceeded those for healthy controls [15].

Biological context of TERF1

• Characterization of the telomere complex, TERF1 and TERF2 genes in muntjac species with fusion karyotypes [16].
• TRF1 is proposed to be an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends [17].
• Here we describe a novel Pin2/TRF1 binding protein, PinX1 that inhibits telomerase activity and affects tumorigenicity [18].
• However, the dimerization domains of TRF1 and TRF2 did not interact, suggesting that these proteins exist predominantly as homodimers [17].
• Overexpression of TRF2 results in the progressive shortening of telomere length, similar to the phenotype observed with TRF1 [19].

Anatomical context of TERF1

• Control experiments disclosed a novel testis-specific splice variant of TERF1 in human testes [16].
• Analysis of rodent spermatocytes reveals Trf1 at mouse, TRF2 at rat, and mammalian Rap1 at meiotic telomeres of both rodents [20].
• Interestingly, Pin2/TRF1 specifically localizes to mitotic spindles in mitotic cells and affects the microtubule polymerization in vitro [21].
• Expression of TRF1 and TRF2 mRNAs was greater in the normal cells than in human malignant hematopoietic cell lines and in 16 samples of patients with acute leukemia [22].
• Of 20 gastric carcinomas examined, 10 (50%) and 12 (60%) expressed TRF1 and TRF2 at higher levels than did non-neoplastic mucosa, respectively [23].

Associations of TERF1 with chemical compounds

• Flow cytometry measurements indicated that the increase of TRF1 and TRF2 proteins is related to oxidative stress by arsenic trioxide [11].
• Tomato TERF1 modulates ethylene response and enhances osmotic stress tolerance by activating expression of downstream genes [12].
• This Pin2/TRF1 activity can be significantly potentiated by the microtubule-disrupting agent nocodazole [12] but is suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is important for preventing apoptosis upon DNA damage [13] [24].
• However, small but significant differences are observed; in contrast to the minor groove recognition of TRF1, in which an arginine residue recognizes the TT sequence, a lysine residue of TRF2 interacts with the TT part [25].
• We identified human nucleoside diphosphate kinase nm23-H2 as a human TRF1-interacting protein by yeast two-hybrid screening [26].
• Phosphorylation of threonine 122 seemed critical for TRF1-mediated telomere length control [27].

Physical interactions of TERF1

• Fbx4 interacts with both Pin2 and TRF1 isoforms and promotes their ubiquitination in vitro and in vivo [28].
• Pin2/TRF1 bound EB1 both in vitro and in vivo and they also co-localize at the mitotic spindle in cells [21].
• Furthermore, POT1 binding was regulated by the TRF1 complex in response to telomere length [29].
• Although each of the five ankyrin repeat clusters independently binds to TRF1, only three of the five bind toTAB182 [30].
• SALL1 has recently been shown to localize to chromocenters and other heterochromatin foci in murine fibroblasts and to interact with the telomere-repeat-binding factor TRF1/PIN2 [31].

Enzymatic interactions of TERF1

• Furthermore, activated ATM directly phosphorylated Pin2/TRF1 preferentially on the conserved Ser(219)-Gln site in vitro and in vivo [32].

Regulatory relationships of TERF1

• The telomeric repeat binding factor TRF1 inhibits telomerase at telomeres in cis in a length-dependent manner to achieve telomere length homeostasis [33].
• Furthermore, EB1 inhibits the ability of Pin2/TRF1 to promote microtubule polymerization in vitro [21].
• TRF1 is known to be eliminated from telomeres by overexpression of tankyrase 1 which induces TRF1 poly(ADP-ribosyl)ation [34].

Other interactions of TERF1

• Thus, in less than 50 PDs, the length of telomeres increased 3-8-fold beyond physiological size, while telomere-bound TRF1 and TRF2 increased proportionally to telomere length [33].
• Interestingly, mouse TRF1 lacks this motif and thus does not bind either tankyrase-1 or -2 [35].
• Herein we describe a novel RXXPDG motif shared by IRAP, TAB182, and human TRF1 that mediates their binding to tankyrases [35].
• Role of human telomerase reverse transcriptase and telomeric-repeat binding factor proteins 1 and 2 in human hematopoietic cells [22].
• Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres [36].
• These results demonstrate that Plk1 interacts with and phosphorylates TRF1 and suggest that Plk1-mediated phosphorylation is involved in both TRF1 overexpression-induced apoptosis and its telomeric DNA binding ability [37].

Analytical, diagnostic and therapeutic context of TERF1

• The expressions of TERF1 and TERF2 mRNA detected by in situ hybridization were scored positive in 36% and 82% of low-grade AAH, 65% and 83% of high-grade AAH, and 88% and 88% of BAC, respectively [1].
• Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts [19].
• Expression analysis revealed that both genes are ubiquitously expressed and sequence analysis identified several transcript variants of both TERF genes [16].
• Surprisingly, dissection of this domain reveals multiple discrete and overlapping binding sites for TRF1 and TAB182 [30].
• PCR and sequencing were used to detect mutation of each exon of hTRF1 in 10 cell line cells [38].

References