Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The invasiveness of cancer cells resembles the normal behavior of cells that migrate into surrounding tissues during development. For example, the border cells in the Drosophila ovary undergo a partial epithelial to mesenchymal transition and invade the neighboring cluster of germline cells, migrating to the oocyte border. Once there, they provide patterning information to the oocyte and produce an eggshell specialization known as the micropyle. Border cell migration has been subjected to extensive genetic analyses using a variety of screening approaches. Recent findings demonstrate that conversion of the border cells from a stationary group of epithelial cells to invasive cells requires integration of the activities of at least two transcriptional regulatory pathways. One such pathway requires the slbo gene, which encodes Drosophila C/EBP, a basic region/leucine zipper transcriptional activator that is required for elevated expression of a number of downstream targets, including DE-cadherin and focal adhesion kinase (FAK). An independent pathway requires the activity of the ecdysone receptor and a recently identified co-activator for the ecdysone receptor known as Taiman (abbreviated TAI, pronounced ti-maan', meaning too slow). Ecdysone is produced in the Drosophila ovary in response to adequate nutrition and is required for progression of oogenesis through stage 9, when border cell migration occurs. Border cells mutant for tai accumulate abnormally high levels of adhesion complexes at their surfaces, which may account for their inability to migrate. Thus border cell migration requires a differentiation program mediated by the C/EBP pathway, which is required for elevated expression of a number of proteins required for motility. In addition, migration requires a hormonal signal that relays information regarding nutritional status and appears to be required for regulation of the proper localization of some of the C/EBP targets. These findings suggest that steroid hormones can regulate cell motility relatively directly, independent of the effects on proliferation. This may contribute to the metastatic effects of steroid hormones on certain cancers and the inhibition of metastasis by steroid hormone antagonists such as tamoxifen.
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PMID:Command and control: regulatory pathways controlling invasive behavior of the border cells. 1142 78

Beta-catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator in the Wnt signalling pathway. Although recent investigations have been focused on the role of the adenomatous polyposis coli (APC)/ beta-catenin/Tcf pathway in human tumorigenesis, there have been very few reports on mutations of the beta-catenin gene in a variety of tumour types. Using PCR and single-strand conformational polymorphism analysis, we examined 93 lung, 9 breast, 6 kidney, 19 cervical and 7 ovarian carcinoma cell lines for mutations in exon 3 of the beta-catenin gene. In addition, we tested these same samples for mutations in the NH2-terminal regulatory region of the gamma-catenin gene. Mutational analysis for the entire coding region of beta-catenin cDNA was also undertaken in 20 lung, 9 breast, 5 kidney and 6 cervical carcinoma cell lines. Deletion of most beta-catenin coding exons was confirmed in line NCI-H28 (lung mesothelioma) and a silent mutation at codon 214 in exon 5 was found in HeLa (cervical adenocarcinoma). A missense mutation at codon 19 and a silent mutation at codon 28 in the NH2-terminal regulatory region of the gamma-catenin gene were found in H1726 (squamous cell lung carcinoma) and H1048 (small cell lung carcinoma), respectively. Neither deletions nor mutations of these genes were detected in the other cell lines examined. These results suggest that beta- and gamma-catenins are infrequent mutational targets during development of human lung, breast, kidney, cervical and ovarian carcinomas.
Br J Cancer 2001 Jul 06
PMID:Mutations of the beta- and gamma-catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas. 1143 3

Autoantibodies to intracellular proteins have been detected in sera of patients with various forms of cancer. Nuclear autoantigen SG2NA (S, G2 phase nuclear antigen) was isolated using autoantibodies from a patient with bladder and lung cancers and its expression is enhanced in the S and G2 phases of the cell cycle. Molecular cloning revealed that the C-terminal region of SG2NA contains six WD-40 repeats, motifs that are present in a large family of proteins with diverse functions. We show that the N-terminal region of SG2NA (aa 1-391) acted as a strong transcriptional activator in both yeast and mammalian cells. In contrast, the C-terminal WD-40 repeats had an inhibitory effect on transcription activation. We performed molecular swapping experiments by substituting the WD-40 repeats of SG2NA with those of yeast Met30 and Cdc4 and showed that the WD-40 regions from either Met30 or Cdc4 were capable of reproducing transcription repression function. The SG2NA WD-40 repeats were also able to repress basal level transcription and transactivation function of a GAL4-VP16 chimera. These observations suggest that some WD-40 repeats may have, as one of their functions, a negative regulatory role in the biological activities of their own and perhaps other proteins.
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PMID:Transcription activating property of autoantigen SG2NA and modulating effect of WD-40 repeats. 1157 Aug 23

Inactivating mutations in the adenomatous polyposis coli (APC) gene correlate with progression of colon cancer and familial adenomatous polyposis. The APC tumor suppressor contributes to chromosome segregation and turnover of the oncogenic transcriptional activator beta-catenin, and these activities are impaired by truncating cancer mutations. APC was recently identified as a shuttling protein whose subcellular distribution is regulated by two nuclear localization signals (NLSs) and multiple nuclear export signals (NESs). Here, we show that mutant disease-linked truncated forms of APC, most of which lack the two central NLSs and certain NES sequences, retain nuclear-cytoplasmic shuttling activity. Nuclear export of truncated APC is mediated by a dominant N-terminal NES. Nuclear import of NLS-deficient APC mutants is facilitated by the N-terminal ARM domain. Furthermore, co-expression of the ARM-binding protein, B56 alpha, increased the nuclear localization of mutant and wild-type APC. The minimal B56 alpha-responsive sequence mapped to APC amino acids 302-625. B56 alpha is a regulatory subunit of protein phosphatase 2A; however, its ability to shift APC to the nucleus was independent of phosphatase activity. We conclude that APC nuclear import is regulated by the ARM domain through its interaction with B56 alpha and postulate that APC/B56 alpha complexes target the dephosphorylation of specific proteins within the nucleus.
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PMID:ARM domain-dependent nuclear import of adenomatous polyposis coli protein is stimulated by the B56 alpha subunit of protein phosphatase 2A. 1158 28

Loss of Dmp1, an Arf transcriptional activator, leads to spontaneous tumorigenesis in mice, causing death from various forms of cancer by two years of age. Retention and expression of the wild-type Dmp1 allele in tumors arising in Dmp1(+/-) mice demonstrate that Dmp1 can be haplo-insufficient for tumor suppression. The mean latency of E(mu)-Myc-induced B-cell lymphomas is halved on a Dmp1(-/-) or Dmp1(+/-) genetic background. Although p53 mutations or Arf deletion normally occur in approximately 50% of E(mu)-Myc-induced lymphomas, Dmp1 loss obviates selection for such mutations, indicating that Dmp1 is a potent genetic modifier of the Arf-p53 pathway in vivo.
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PMID:Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas. 1171 28

The migration-inducing gamma2 chain of laminin-5, one of the best known invasion markers, is strongly overexpressed in disseminating and infiltrating tumor cells at the invasive front of colorectal carcinomas. The same tumor cells show nuclear accumulation of the oncoprotein beta-catenin, which together with T-cell factor-DNA-binding proteins, functions as transcriptional activator of genes involved in tumor progression. Here we show that beta-catenin activates the human laminin-5 gamma2 gene through two T-cell factor-binding elements in a synergistic manner together with hepatocyte growth factor and conclude that laminin-5 gamma2 is another important target gene of nuclear beta-catenin during tumor progression.
Cancer Res 2001 Nov 15
PMID:Expression of the invasion factor laminin gamma2 in colorectal carcinomas is regulated by beta-catenin. 1171 33

Prostate Specific Ets factor is a recently identified transcriptional activator that is overexpressed in prostate cancer. To determine whether this gene is overexpressed in breast cancer, we performed a virtual Northern blot using data available online at the Cancer Genome Anatomy Project website. Ninety-five SAGE libraries were probed with a unique sequence tag to the Prostate Specific Ets gene. The results indicate that Prostate Specific Ets is expressed in 14 out of 15 breast cancer libraries (93%), nine out of 10 prostate cancer libraries (90%), three out of 40 libraries from other cancers (7.5%), and four out of 30 normal tissue libraries (13%). To determine the possibility that the Prostate Specific Ets gene is a novel marker for detection of metastatic breast cancer in axillary lymph nodes, quantitative real-time RT-PCR analyses were performed. The mean level of Prostate Specific Ets expression in lymph nodes containing metastatic breast cancer (n=22) was 410-fold higher than in normal lymph node (n=51). A receiver operator characteristic curve analysis indicated that Prostate Specific Ets was overexpressed in 18 out of 22 lymph nodes containing metastatic breast cancer (82%). The receiver operator characteristic curve analysis also indicated that the diagnostic accuracy of the Prostate Specific Ets gene for detection of metastatic breast cancer in axillary lymph nodes was 0.949. These results provide evidence that Prostate Specific Ets is a potentially informative novel marker for detection of metastatic breast cancer in axillary lymph nodes, and should be included in any study that involves molecular profiling of breast cancer.
Br J Cancer 2002 Mar 18
PMID:Prostate-Specific Ets (PSE) factor: a novel marker for detection of metastatic breast cancer in axillary lymph nodes. 1195 21

Growth factor receptors mediate cell signaling events that regulate a diverse array of cellular activities including cell proliferation, homeostasis, and differentiation of both normal and cancer cells. Studies of the mechanisms governing transcription of growth factor receptor genes have revealed common structural features of their promoters. These common features include GC rich promoter regions and multiple Sp factor binding sites based upon which most of these promoters are transactivated. Mechanisms of growth factor receptor promoter activation via these common structural features will be reviewed, with particular attention to control of FGFR1 promoter activity in skeletal muscle cells. Of equal importance in cellular function is the repression of growth factor receptor signaling and gene expression. Mechanisms that repress growth factor receptor promoter activity operate via direct repression at transcriptional activator binding sites and via protein-protein interactions that abrogate activator function. Mechanisms of growth factor receptor transcriptional repression will be considered in the context of known tumor suppressors, transcription activator availability, as well as in light of emerging potential Sp1-like transcriptional repressors.
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PMID:Activation and repression of growth factor receptor gene transcription (Review). 1206 Aug 52

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus is linked to Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), all of which are viewed as cytokine-driven malignancies. In particular, interleukin-6 (IL-6) has been found to promote the growth and proliferation of cells from KS and PEL. HHV-8 encodes a homologue of IL-6 (viral IL-6 [vIL-6]), which functions similarly to the cellular IL-6. Therefore, vIL-6 has been proposed to play an important role in tumor progression. Several groups have reported that vIL-6 is expressed from the HHV-8 genome at higher levels in PEL and MCD lesions than in KS lesions. However, it is not clear how vIL-6 expression is regulated. We characterized the transcription at the vIL-6 gene locus by Northern blot analysis and, in contrast to previous reports, we observed two distinct transcripts from induced PEL cell lines. This observation was confirmed by primer extension, as well as 5' and 3' rapid amplification of cDNA ends. Two transcription initiation sites and putative TATA boxes were mapped. A luciferase reporter system was used to show that each of the two putative TATA boxes contributed to vIL-6 promoter activity. Since virally encoded transcriptional activator Rta potently activates the viral lytic gene expression cascade, we examined the role of Rta in controlling vIL-6 gene expression and found that Rta activated the vIL-6 promoter. The Rta-responsive element was further mapped through a series of deletion constructs. Electrophoretic mobility shift assays demonstrated that Rta binds directly to the vIL-6 Rta-responsive element, and the core Rta-responsive element was mapped to a 26-bp region spanning from nucleotide 18315 to 18290 on the viral genome. We propose that the existence of two vIL-6 promoters offers opportunities for differential regulation of vIL-6 gene expression in different tissue types and may account for the variable vIL-6 levels observed in KS, PEL, and MCD.
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PMID:Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus). 1213 31

Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus (KSHV) is linked to a number of malignancies thought to be driven by cytokines, including interleukin-6 (IL-6). Rta, a transcriptional activator encoded by HHV-8/KSHV, activates the viral lytic cycle leading to the expression of several viral genes implicated in viral pathogenesis. However, the effect of HHV-8/KSHV Rta on cellular genes has not been reported. We present evidence that the human IL-6 (hIL-6) gene is up-regulated by Rta. Rta potently activated (up to 164-fold) the hIL-6 promoter in a dose-dependent manner in a transient transfection reporter system. Rta also induced expression of the endogenous hIL-6 gene, as shown by enzyme-linked immunosorbent assays. Activation of the hIL-6 gene by HHV-8/KSHV supports the role of hIL-6 in the development of these malignancies.
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PMID:Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up-regulates human interleukin-6 gene expression. 1217 19


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