Chiral (phosphine)-(imidazoline) PCN pincer palladium(II) complexes: synthesis and application in asymmetric hydrophosphination of 2-alkenoylpyridines with diphenylphosphine.

A series of new chiral PCN pincer Pd(II) complexes 3a-l with aryl-based (phosphine)-(imidazoline) ligands were conveniently synthesized from readily available starting materials with the key step being phosphination/C-H palladation reaction. All of the new complexes were characterized by H NMR, C{H} NMR, P{H} NMR, and elemental analysis. In addition, the molecular structures of complexes 3c, 3e, 3i, and 3k have been determined by X-ray single crystal diffraction analysis.

The PinX1/NPM interaction associates with hTERT in early-S phase and facilitates telomerase activation.

Background: Telomere maintenance is an important factor in tumorigenesis. PinX1 is a potent telomerase regulator which also involves in telomerase loading to telomeres. Nucleophosmin (NPM) can partially attenuate PinX1 inhibition of telomerase activity and NPM loading to hTERT requires PinX1.

Nucleophosmin Interacts with PIN2/TERF1-interacting Telomerase Inhibitor 1 (PinX1) and Attenuates the PinX1 Inhibition on Telomerase Activity.

Telomerase activation and telomere maintenance are critical for cellular immortalization and transformation. PIN2/TERF1-interacting telomerase inhibitor 1 (PinX1) is a telomerase regulator and the aberrant expression of PinX1 causes telomere shortening. Identifying PinX1-interacting proteins is important for understanding telomere maintenance.

The putative oncotarget CSN5 controls a transcription-uncorrelated p53-mediated autophagy implicated in cancer cell survival under curcumin treatment.

Curcumin has shown promise as a safe and specific anticancer agent. The COP9 signalosome (CSN) component CSN5, a known specific target for curcumin, can control p53 stability by increasing its degradation through ubiquitin system. But the correlation of CSN5-controlled p53 to anticancer therapeutic effect of curcumin is currently unknown.

Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation.

Aims: Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation.

Inhibition of hepatocellular carcinoma growth by adenovirus-mediated expression of human telomerase reverse transcriptase COOH-27 terminal polypeptide in mice.

A 27-kDa C-terminal fragment of human telomerase reverse transcriptase, hTERTC27, has previously been reported to inhibit the growth and tumorigenicity of HeLa human cervical cancer cells and U87-MG human glioblastoma multiforme cells. However, the antitumor effects of hTERTC27 in hepatoma and its underlying mechanisms are unclear. In the current study, the therapeutic effect of hTERTC27, mediated by recombinant adenovirus, in hepatocellular carcinoma (HCC) was explored and to investigate the possible mechanisms.

Preclinical safety evaluation of rAd5-hTERTC27 by intravenous injection.

The safety of rAd5-hTERTC27, a replication defective adenovirus vector carrying hTERTC27 for possible use against hepatocellular carcinoma (HCC) was assessed. In single-dose evaluations, intravenous dose levels of up to 2×10(11)VP/kg in rats and 9×10(10)VP/kg in monkeys were well tolerated with no abnormal changes in general signs, body weight and food consumption, and no significant differences in biochemical parameters, urinalysis, ECG, and systemic necropsy observations between the rAd5 groups and solvent control group except that slight hematological change was observed. No hemolytic effect using rabbit blood, local perivasculitis following intravenous injection in rabbits or systemic anaphylaxis in guinea pigs following intravenous dosing was seen.

The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas.

Chemoradiotherapy (CRT) is a standard treatment for oesophageal squamous cell carcinoma (ESCC) in its advanced stages. The telomerase/telomere interacting protein PinX1 contributes to telomere maintenance, tumourigenicity, and influences the DNA damage agent-induced apoptotic response in telomerase-positive cancer cells. However, the clinical and biological significance of PinX1 in human ESCCs remains unclear.

PinX1 is involved in telomerase recruitment and regulates telomerase function by mediating its localization.

Telomerase recruitment to telomere is the prerequisite for telomere extension, but the proteins involved in this process are still largely unknown. PinX1 is a telomerase inhibitor and has been implicated in telomere maintenance. Silencing of PinX1 significantly reduced the localization of telomerase to telomere during mid-late S phase, suggesting the involvement of PinX1 in the cell cycle-dependent trafficking of hTERT to telomere.

Effective antitumor immunity against murine gliomas using dendritic cells transduced with hTERTC27 recombinant adenovirus.

hTERTC27, a 27-kDa hTERT C-terminal polypeptide has been demonstrated to cause hTERT-positive HeLa cell apoptosis and inhibits the growth of mouse melanoma. hTERTC27 has been associated with telomere dysfunction, regulation of gene-regulated apoptosis, the cell cycle and activation of natural killer (NK) cells, but its mechanism of action is not fully understood. Here, we report that dendritic cells (DCs) transduced with hTERTC27 can increase T-cell proliferation, and augment the concentration of interleukin-2 (IL-2) and interferon-γ (IFN-γ) in the supernatants of T cells.

Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells.

The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening-induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status.

Nucleolar localization of TERT is unrelated to telomerase function in human cells.

Telomerase maintains telomere length and has been implicated in both aging and carcinogenesis of human cells. This enzyme is a specialized ribonucleoprotein (RNP) complex, minimally consisting of two essential components: the protein catalytic subunit TERT (telomerase reverse transcriptase) and the integral RNA moiety TR (telomerase RNA, TERC). Both TERT and TR have been found to localize to nucleoli within the nucleus, leading to the suggestion of nucleoli as the site for telomerase RNP biogenesis in human cells.

Characterization of a novel effect of hPinX1 on hTERT nucleolar localization.

The factor PinX1 has been shown as a telomerase inhibitor evolutionarily conserved in both the yeast and the human being. yPinX1 inhibits telomerase activity by sequestering yTERT (telomerase reverse transcriptase) from uniting with yTR (telomerase template RNA) in the nucleolus of yeast cells. However, the mechanism underlying the action of hPinX1 on telomerase regulation in human cells is not known.

Cancer immunotherapy targeting the telomerase reverse transcriptase.

The human telomerase reverse transcriptase (hTERT) is expressed in more than 85% of tumor cells but is usually not found in normal cells, which makes hTERT as an ideal tumor-associate antigen (TAA) to develop potential vaccine specifically destroying cancers without impairing normal tissues in human cancer immunotherapy. Here are reviewed the fundamental advances of studies on immunogenicity of hTERT or its peptides and the early clinical trials using the hTERT vaccine approach in the last decades.

Expression of a recombinant vector of a mutant human telomerase reverse transcriptase gene in human bladder cancer cell line T24, and its clinical significance.

Objective: To construct a mutant enhanced green fluorescence protein (pEGFP) human telomerase reverse transcriptase (hTERT) gene expression vector (pEGFP-hTERT), to observe its expression in transfected human bladder cancer cell line T24 and its role in the molecular regulatory mechanisms of telomerase, and to provide a new target gene for bladder cancer therapy.

Materials And Methods: Polymerase chain reaction (PCR) amplification was performed using primers based on the gene sequence of hTERT. The PCR product was cloned into plasmid pGEMT-T Easy and the sequence of mutant hTERT gene analysed.

A human TERT C-terminal polypeptide sensitizes HeLa cells to H2O2-induced senescence without affecting telomerase enzymatic activity.

We have constructed a 27-kDa hTERT C-terminal polypeptide (hTERTC27) devoid of domains required for telomerase activity and demonstrated that it is capable of nuclear translocation/telomere-end targeting. Here we showed that expression of a low level of hTERTC27 renders hTERT positive HeLa cells sensitive to H(2)O(2)-induced oxidative stress and subsequent cell senescence. The senescence-associated gene, the cyclin/cdk inhibitor p21(Waf1), was up-regulated.

Ectopic expression of a COOH-terminal fragment of the human telomerase reverse transcriptase leads to telomere dysfunction and reduction of growth and tumorigenicity in HeLa cells.

The COOH-terminus of telomerase reverse transcriptase (hTERT) has been shown to participatein the nuclear translocation of TERT. Here, we constructed plasmids expressing the COOH-terminal M(r) 27,000 polypeptide of hTERT (hTERTC27) withthe telomerase RNA-binding domains and the reverse transcriptase domains deleted. We showed that ectopic overexpression of this polypeptide caused a defect in telomere maintenance in hTERT-positive HeLa cells, which led to senescence-like growth arrest and apoptosis.