Maintenance of telomeres is implicated in chromosome stabilization and cell immortalization. Telomerase, which catalyzes de novo synthesis of telomeres, is activated in germ cells and most cancers. Telomerase activity is regulated by gene expression for its catalytic subunit, TERT, whereas several lines of evidence have suggested a post‐translational regulation of telomerase activity. Here we identify the 14‐3‐3 signaling proteins as human TERT (hTERT)‐binding partners. A dominant‐negative 14‐3‐3 redistributed hTERT, which was normally predominant in the nucleus, into the cytoplasm. Consistent with this observation, hTERT‐3A, a mutant that could not bind 14‐3‐3, was localized into the cytoplasm. Leptomycin B, an inhibitor of CRM1/exportin 1‐mediated nuclear export, or disruption of a nuclear export signal (NES)‐like motif located just upstream of the 14‐3‐3 binding site in hTERT impaired the cytoplasmic localization of hTERT. Compared with wild‐type hTERT, hTERT‐3A increased its association with CRM1. 14‐3‐3 binding was not required for telomerase activity either in vitro or in cell extracts. These observations suggest that 14‐3‐3 enhances nuclear localization of TERT by inhibiting the CRM1 binding to the TERT NES‐like motif.
Telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 poly(ADP-ribosyl)ates TRF1 and releases it from telomeres, allowing access of telomerase to telomeres. Here we demonstrate that tankyrase 1 inhibition in human cancer cells enhances telomere shortening by a telomerase inhibitor and hastens cell death. Conversely, either tankyrase 1 upregulation or telomere shortening, each of which decreased TRF1 loading on a chromosome end, attenuated the impact of telomerase inhibition. These results are consistent with the idea that telomeres having fewer TRF1s increase the efficiency of their elongation by telomerase. This study implies that both enzyme activity and accessibility to telomeres can be targets for telomerase inhibition.
In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the () gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form mutations predict the sensitivity of colorectal cancer cells to tankyrase inhibitors. By using well-established colorectal cancer cell lines, we found that tankyrase inhibitors downregulated β-catenin in the drug-sensitive, but not resistant, colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed "short" truncated APCs lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long" APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased β-catenin, Tcf/LEF transcriptional activity and its target gene expression. Under these conditions, tankyrase inhibitors were able to downregulate β-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent β-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived colorectal cancer cells and confirmed that the tankyrase inhibitor-responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics..
Poly(4,4‘-dialkyl-2,2‘-bithiazole-5,5‘-diyl)s (PRBTz, alkyl
= methyl (PMeBTz), butyl (PBuBTz),
and heptyl (PHepBTz)) and their analogues comprised of 33−150
thiazole rings have been
prepared by organometallic polycondensation, and their chemical and
physical properties
are compared with those of π-conjugated poly(thiophene-2,5-diyl)
(PTh) and poly(pyridine-2,5-diyl) (PPy). Electrochemical n-doping of PRBTz takes place at
E° = −1.77 to −2.30 V
vs Ag/Ag+ and is accompanied by the appearance of a new
absorption band in the near-infrared. PMeBTz assumes a relatively stiff structure in solution
and shows a large refractive
index increment of 0.55 cm3 g-1;
powder X-ray diffraction analysis of PMeBTz supports a
face-to-face type stacking of the polymer chains in the solid state.
All of the polymers show
photoluminescence in solutions and in the solid, and an
electroluminescence device using
PMeBTz as the emitting layer gives emission of light at
λmax = 680 nm with 100 cd m-2
at
8 V. A thin film of PMeBTz gives an optical third-order nonlinear
susceptibility χ(3) of 2.5
× 10-11 esu, which is larger than observed
with PTh and PPy films, and comparison of the
χ(3) value with that (0.3 ×
10-11 esu) of nonregioregular
poly(4-methylthiazole-2,5-diyl)
(PMeTz) reveals the importance of the regioregular structure of PMeBTz
to give the larger
χ(3) value.
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