Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q02556 (DNA-binding domain)
 6,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen receptor beta (ERbeta) is the predominant ER in the colorectal epithelium. Compared with normal colon tissue, ERbeta expression is reduced in colorectal cancer. Our hypothesis is that ERbeta inhibits proliferation of colon cancer cells. Hence, the aim of this study has been to investigate the molecular function of ERbeta in colon cancer cells, focusing on cell cycle regulation. SW480 colon cancer cells have been lentivirus transduced with ERbeta expression construct with or without mutated DNA-binding domain or an empty control vector. Expression of ERbeta resulted in inhibition of proliferation and G(1) phase cell cycle arrest and this effect was dependent on a functional DNA-binding region. c-Myc is overexpressed in an overwhelming majority of colorectal tumors. By Western blot and real-time PCR, we found c-Myc to be down-regulated in the ERbeta-expressing cells. Furthermore, the c-Myc target gene p21((Waf1/Cip1)) was induced and Cdc25A was reduced by ERbeta at the transcriptional level. The second cdk2-inhibitor, p27(Kip1), was induced by ERbeta, but this regulation occurred at the posttranscriptional level, probably through ERbeta-mediated repression of the F-box protein p45(Skp2). Expression of the ERbeta-variant with mutated DNA binding domain resulted in completely different cell cycle gene regulation. We performed in vivo studies with SW480 cells +/- ERbeta transplanted into severe combined immunodeficient/beige mice; after three weeks of ERbeta-expression, a 70% reduction of tumor volume was seen. Our results show that ERbeta inhibits proliferation as well as colon cancer xenograft growth, probably as a consequence of ERbeta-mediated inhibition of cell-cycle pathways. Furthermore, this ERbeta-mediated cell cycle repression is dependent on functional ERE binding.
 ...
PMID:Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells. 1960 91

The largest subunit of the mammalian SWI/SNF-A or BAF (BRG1-associated factor) chromatin-remodelling complex is encoded by two related cDNAs hOsa1/BAF250a and hOsa2/BAF250b that are unique to the BAF complex and absent in the related PBAF (Polybromo BAF). hOsa/BAF250 has been shown to interact with transcriptional activators and bind to DNA suggesting that it acts to target the remodelling complex to chromatin. To better understand the functions of hOsa2, we established inducible stable HeLa cell lines over-expressing FLAG-hOsa2 or a derivative lacking the ARID (AT-rich interactive domain) DNA-binding domain. Immunopurification of complexes containing hOsa2 that was followed by mass spectrometry and immunoblotting demonstrated the presence of BRG1 and known BAFs, but not hOsa1 or hBRM. Deletion of the ARID did not compromise the integrity of the complex. Induction of hOsa2 expression caused impaired cell growth and accumulation of cells in the G0/G1 cell cycle phase. Elevated levels of the p53 and p21 proteins were detected in these cells while c-Myc mRNA and protein levels were found to decrease. Chromatin immunoprecipitation and reporter assays suggested that hOsa2 had a direct effect on c-myc and p21 promoter activity. Thus hOsa2 plays an important role in controlling genes regulating the cell cycle.
 ...
PMID:Target genes of the largest human SWI/SNF complex subunit control cell growth. 2111 56

Pluripotency and self-renewing ability of embryonic stem (ES) cells are regulated by several transcription factors, including Oct3/4, Sox2, Kruppel-like factor 4 (Klf4), and c-Myc. These transcription factors reprogram somatic cells into induced pluripotent stem (iPS) cells. Zinc finger protein (Zfp) 296 has been reported to enhance iPS cell formation. Here we found that Zfp296 interacts with Klf4. A maltose-binding protein pull-down assay demonstrated that Klf4 binds to the Zfp296 158-483 amino acid region, and that Zfp296 binds to the Klf4 DNA-binding domain (DBD). A quantitative reverse transcription-polymerase chain reaction analysis revealed that expression of Zfp296 and Klf4 decreased during differentiation of E14 and ZHBTc4 ES cells. We also found that green fluorescent protein-labeled Zfp296 and Klf4 were localized to the nucleus. Because Zfp296 bound to the Klf4 DBD, we next examined the influence of Zfp296 on Klf4 DNA-binding activity. A biotin DNA pull-down assay showed that Klf4 binds to the Lefty1 promoter region, and that binding activity was sustained even in the presence of Zfp296. In contrast, a reporter assay showed that the Lefty1 promoter was activated by Klf4, and that the enhanced activity was repressed by Zfp296. These findings suggest that Zfp296 is a functional regulator of Klf4 in ES cells.
...
PMID:Zfp296 is a novel Klf4-interacting protein and functions as a negative regulator. 2416 96

The Myc transcription factor represents an "undruggable" target of high biological interest due to its central role in various cancers. An abbreviated form of the c-Myc protein, called Omomyc, consists of the Myc DNA-binding domain and a coiled-coil region to facilitate dimerization of the 90 amino acid polypeptide. Here we present our results to evaluate the synthesis of Omomyc using three complementary strategies: linear Fmoc solid-phase peptide synthesis (SPPS) using several advancements for difficult sequences, native chemical ligation from smaller peptide fragments, and a high-throughput bacterial expression and assay platform for rapid mutagenesis. This multifaceted approach allowed access to up to gram quantities of the mini-protein and permitted in vitro and in vivo SAR exploration of this modality. DNA-binding results and cellular activity confirm that Omomyc and analogues presented here, are potent binders of the E-box DNA engaged by Myc for transcriptional activation and that this 90-amino acid mini-protein is cell permeable and can inhibit proliferation of Myc-dependent cell lines. We also present additional results on covalent homodimerization through disulfide formation of the full-length mini-protein and show the coiled-coil region can be truncated while preserving both DNA binding and cellular activity. Altogether, our results highlight the ability of advanced peptide synthesis to achieve SAR tractability in a challenging synthetic modality.
 ...
PMID:Multiple Synthetic Routes to the Mini-Protein Omomyc and Coiled-Coil Domain Truncations. 3166 Jul 43

Signal transducer and activator of transcription 3 (STAT3) is expressed aberrantly in multiple tumors, including gastric cancer (GC). STAT3 overexpression and excessive activation have been confirmed to play vital roles in tumorigenesis. Cucurbitacin B (CuB) is a natural product with potent anti-cancer activities in solid tumors. Here, we systematically studied the underlying molecular mechanisms of CuB inhibition of GC both in vitro and in vivo. In GC cell lines, nanomolar concentrations of CuB decreased the phosphorylation of TYR-705 in STAT3 and suppressed STAT3 target gene expression, including c-Myc and Bcl-xL. Computational docking analysis showed that CuB interacts with the DNA-binding domain of STAT3 at several hydrophobic residues. In addition, pull-down experiments showed that CuB is a direct inhibitor of STAT3. CuB in combination with the conventional chemotherapy drug cisplatin exerted enhanced cytotoxicity in GC cells, possibly due to the potentiated inhibition of STAT3 activation. Moreover, a xenograft mouse model confirmed the therapeutic effect of CuB in vivo. These characteristics render CuB a promising candidate drug for further development in the design of new effective STAT3 inhibitors for treating GC.
 ...
PMID:Cucurbitacin B inhibits gastric cancer progression by suppressing STAT3 activity. 3208 20


<< Previous 1 2 3