PubMed Health⌕ Search

Biomedical subjects

X Q Qin

Publications and source records attributed to X Q Qin.

10 recordsLinked to original sources
PubMed1998

Interferon-beta gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice.

Despite the potential of type 1 interferons (IFNs) for the treatment of cancer, clinical experience with IFN protein therapy of solid tumors has been disappointing. IFN-beta has potent antiproliferative activity against most human tumor cells in vitro in addition to its known immunomodulatory activities. The antiproliferative effect, however, relies on IFN-beta concentrations that cannot be achieved by parenteral protein administration because of rapid protein clearance and systemic toxicities. We demonstrate here that ex vivo IFN-beta gene transduction by a replication-defective adenovirus in as few as 1% of implanted cells blocked tumor formation. Direct in vivo IFN-beta gene delivery into established tumors generated high local concentrations of IFN-beta, inhibited tumor growth, and in many cases caused complete tumor regression. Because the mice were immune-deficient, it is likely that the anti-tumor effect was primarily through direct inhibition of tumor cell proliferation and survival. Based on these studies, we argue that local IFN-beta gene therapy with replication-defective adenoviral vectors might be an effective treatment for some solid tumors.

Adenoviridae↗
PubMed1997

Differential cell cycle effects induced by E2F1 mutants.

Expression of two types of transactivation-defective E2F1 mutants in human Rb-/- tumor cells led to an increase in the proportion of cells in the G1 phase of the cell cycle as determined by FACS analysis. Experiments revealed two different mechanisms of action. One mutant type induced a G1 arrest after the restriction point, with cells phenotypically at a cell cycle stage later than G1. The action of this mutant was, at least in part, dependent on specific DNA binding and was over-ridden by co-expression of its wild-type counterpart. The other mutant type, which is defective in DNA binding, slowed the G1 progression and restored a checkpoint for cell cycle withdrawal. The G1 phase withdrawal of these tumor cells allowed the initiation of skeletal muscle cell differentiation. Thus, E2F1 appears to have two different functions before and after the cell cycle restriction point. This report also may provide a basis for a gene therapy approach for certain human cancers.

Carrier Proteins↗
PubMed1997

Interferon-beta induces S phase accumulation selectively in human transformed cells.

Interferons (IFNs) generally have been characterized as antiproliferative cytokines. The cell cycle arrest in G1/G0 phase induced by type I IFNs, especially IFN-alpha, was recognized as a manifestation of their antiproliferative effects. In this article, we report that the cell cycle block in G1/G0 is observed mainly in certain cell types, such as Daudi Burkitt's lymphoma cells. In a variety of human transformed cells, but not nontransformed primary cells, IFN-beta and IFN-alpha induced a significant increase in the S phase population. The increase appeared to be due to a continued S phase entry and subsequently a failure of S phase cells to transit efficiently into G2 and M phases. The ability of tumor cells to exhibit the S phase effect correlated with proper IFN signaling and loss or inactivation of the normal G1 checkpoint conferred by the retinoblastoma protein (pRB). Overriding the G1 checkpoint switched human nontransformed primary cells from nonresponsive to sensitive to the IFN-induced effect. Therefore, the cell cycle regulatory machinery could function, at least in part, as a determining factor that affects the IFN-induced cell cycle effect. The IFN effect in transformed cells may suggest intriguing prospects for combinatorial therapies for cancer.

Cell Cycle↗
PubMed1996

[Cytoprotective effect of epidermal growth factor on cultured rabbit airway epithelial cells exposed to ozone].

In this study, it was observed that ozone (O3) exposure has cytotoxic effects on cultured airway epithelial cells, which was positively related with exposure duration. Both the production of malondialdehyde (MDA) and the 3H release in the exposure group were much higher than the control (P < 0.01), suggesting that lipoperoxidation occurring in the cell membrane was responsible for the cellular injury observed under O3 attack. EGF at low concentration (5 ng/ml) showed cytoprotective effect on airway epithelial cells exposed to O3 as shown by attenuated MDA production and decrease of 3H release and cytotoxic index (P < 0.01). Pretreatment with EGF could reverse the depletion of intracellular GSH content as a result of O3 exposure and increase the total glutathionein the cells. The above results suggest that the cytoprotection of EGF on airway epithelial cells may be related to its promotive effect on GSH synthesis.

Animals↗
PubMed1995

The transcription factor E2F-1 is a downstream target of RB action.

Reintroduction of RB into SAOS2 (RB-/-) cells causes a G1 arrest and characteristic cellular swelling. Coexpression of the cellular transcription factor E2F-1 could overcome these effects. The ability of E2F-1 to bind to RB was neither necessary nor sufficient for this effect, and S-phase entry was not accompanied by RB hyperphosphorylation under these conditions. Furthermore, E2F-1 could overcome the actions of a nonphosphorylatable but otherwise intact RB mutant. These data, together with the fact that RB binds to E2F-1 in vivo, suggest that E2F-1 is a downstream target of RB action. Mutational analysis showed that the ability of E2F-1 to bind to DNA was necessary and sufficient to block the formation of large cells by RB, whereas the ability to induce S-phase entry required a functional transactivation domain as well. Thus, the induction of a G1 arrest and the formation of large cells by RB in these cells can be genetically dissociated. Furthermore, the ability of the E2F-1 DNA-binding domain alone to block one manifestation of RB action is consistent with the notion that RB-E2F complexes actively repress transcription upon binding to certain E2F-responsive promoters. In keeping with this view, we show here that coproduction of an E2F1 mutant capable of binding to DNA, yet unable to transactivate, is sufficient to block RB-mediated transcriptional repression.

Base Sequence↗
PubMed1994

Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.

E2F-1 is a transcription factor suspected of activating genes required for S phase and a known target for the action of RB, the retinoblastoma gene product. Its induction in quiescent fibroblasts led to S-phase entry followed by apoptosis. E2F-1-mediated apoptosis was suppressed by coexpression of wild-type RB or a transdominant negative mutant species of p53. In contrast, coexpression of a naturally occurring loss-of-function RB mutant or wild-type p53 did not suppress the induction of apoptosis under these conditions. Thus, deregulated E2F-1 activity gives rise to proliferative and apoptotic signals. p53 appears to participate in the execution of the latter.

Animals↗
PubMed1994

Probing the role of histidine-372 in zinc binding and the catalytic mechanism of Escherichia coli alkaline phosphatase by site-specific mutagenesis.

In the X-ray structure of Escherichia coli alkaline phosphatase at 2.0-A resolution, His-372 was found only 3.8 A away from the zinc and forms a hydrogen-bonding interaction with Asp-327, a bidentate ligand of the zinc at the M1 site. However, His-372 does not directly interact with the zinc atom at the M1 site. In order to investigate the role of the side chain of His-372 in zinc binding and the catalytic mechanism of Escherichia coli alkaline phosphatase, site-directed mutagenesis was used to convert His-372 to alanine. The fact that the His-372-->Ala enzyme has similar zinc binding affinity as the wild-type enzyme indicates that His-372 is not involved in zinc binding at the M1 site. However, the altered kinetic behavior of the mutant enzyme compared to the wild-type enzyme suggests that the imidazole ring of His-372 plays an indirect role in the catalytic mechanism of the enzyme. The hydrolysis activity of the His-372-->Ala enzyme at pH 8.0 is 10-fold lower than that of the wild-type enzyme. In the presence of a phosphate acceptor at pH 8.0, the mutant enzyme is approximately 80% as active as the wild-type enzyme. Therefore, the His-372-->Ala mutation selectively enhances the transphosphorylation activity of the enzyme. The His-372-->Ala enzyme also exhibits 4- and 30-fold decreases in Km as compared to the wild-type enzyme in 0.1 M MOPS buffer and 1.0 M Tris, buffer at pH 8.0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1992

Identification of a growth suppression domain within the retinoblastoma gene product.

To date, all naturally occurring retinoblastoma susceptibility gene (RB) mutations known to be compatible with stable protein expression map to the T/E1A and cellular protein-binding region (the "pocket" domain). This domain extends from residue 379 to 792. When full-length RB and certain truncated forms were synthesized in human RB -/- cells, we found that the minimal region necessary for overt growth suppression extended from residue 379 to 928. A functional pocket domain and sequences extending from the carboxy-terminal boundary of the pocket to the carboxyl terminus of the protein were both necessary for growth suppression. Both sets of sequences were also required for E2F binding; hence, the two functions may be linked.

Adenovirus Early Proteins↗
PubMed1991

A link between double-strand break-related repair and V(D)J recombination: the scid mutation.

We show here that mammalian site-specific recombination and DNA-repair pathways share a common factor. The effects of DNA-damaging agents on cell lines derived from mice homozygous for the scid (severe combined immune deficiency) mutation were studied. Surprisingly, all scid cell lines exhibited a profound hypersensitivity to DNA-damaging agents that caused double-strand breaks (x-irradiation and bleomycin) but not to other chemicals that caused single-strand breaks or cross-links. Neutral filter elution assays demonstrated that the x-irradiation hypersensitivity could be correlated with a deficiency in repairing double-strand breaks. These data suggest that the scid gene product is involved in two pathways: DNA repair of random double-strand breaks and the site-specific and lymphoid-restricted variable-(diversity)-joining [V(D)J] DNA rearrangement process. We propose that the scid gene product performs a similar function in both pathways and may be a ubiquitous protein.

Animals↗