Suppressor Role (suppressor + role)

Distribution by Scientific Domains

Selected Abstracts

The von Hippel-Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma

Jasmien Hoebeeck
Abstract Deletions of the short arm of chromosome 3 are often observed in a specific subset of aggressive neuroblastomas (NBs) with loss of distal 11q and without MYCN amplification. The critical deleted region encompasses the locus of the von Hippel-Lindau gene (VHL, 3p25). Constitutional loss of function mutations in the VHL gene are responsible for the VHL syndrome, a dominantly inherited familial cancer syndrome predisposing to a variety of neoplasms, including pheochromocytoma. Pheochromocytomas are, like NB, derived from neural crest cells, but, unlike NB, consist of more mature chromaffin cells instead of immature neuroblasts. Further arguments for a putative role of VHL in NB are its function as oxygen sensitizer and the reported relation between hypoxia and dedifferentiation of NB cells, leading to a more aggressive phenotype. To test the possible involvement of VHL in NB, we did mRNA expression analysis and sought evidence for VHL gene inactivation. Although no evidence for a classic tumor suppressor role for VHL in NB could be obtained, a strong correlation was observed between reduced levels of VHL mRNA and low patient survival probability (p = 0.013). Furthermore, VHL appears to have predictive power in NTRK1 (TRKA) positive tumor samples with presumed favorable prognosis, which makes it a potentially valuable marker for more accurate risk assessment in this subgroup of patients. The significance of the reduced VHL expression levels in relation to NB tumor biology remains unexplained, as functional analysis demonstrated no clear effect of the reduction in VHL mRNA expression on protein stability of its downstream target hypoxia-inducible factor ,. 2006 Wiley-Liss, Inc. [source]

Regulating p73 isoforms in human tumours

PJ Coates
Abstract Although mutations in the TP73 gene are extremely rare in human tumours, altered expression is common. In some tumours, most notably leukaemias and lymphomas, expression of TP73 is reduced, suggesting a tumour suppressor role. In contrast, TP73 is over-expressed in many other tumour types, implying that it has oncogenic functions in human tumourigenesis. These conflicting scenarios can be reconciled by the observations that the TP73 gene produces p53-like isoforms (TAp73) and anti-p53 isoforms (,TAp73). Thus, loss of TAp73 or over-expression of ,TAp73 should each promote oncogenic transformation, and the balance of expression of the opposing isoforms is the crucial factor. The mechanisms that regulate expression of TP73 isoforms are therefore of great interest. Recent data provide evidence for interacting roles of ZEB1, p300, and a polymorphic 73 bp deletion in intron 1 of the human TP73 gene in this process. Importantly, alterations to the proposed regulatory pathway for controlling TP73 isoform expression in colorectal cancer are associated with adverse clinico-pathological characteristics. Because p73 is also associated with tumour chemosensitivity, these new findings should provide prognostic information and have the potential to guide future therapeutic decisions. Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source]

Allergic contact dermatitis to basic red 46 occurring in an HIV-positive patient

Nathan Curr
SUMMARY A 41-year-old HIV-positive man presented with a 2-month history of a generalized pruritic rash, which had started on his feet. Patch testing made a diagnosis of allergic contact dermatitis to the textile dye basic red 46, likely to have been present in his dark-blue-coloured socks. Complete resolution of his symptoms occurred with avoidance of these socks. The patient had developed allergic contact dermatitis with a low CD4 T lymphocyte count of 361 cells/l (normal range 410,1545 cells/l). This raised the question of the level of CD4 count necessary for an individual to develop allergic contact dermatitis to an allergen, given its role in delayed hypersensitivity. It was concluded that a low CD4 count as a result of HIV infection does not decrease the ability of an individual to develop allergic contact dermatitis. Whereas the effector role in delayed type 4 hypersensitivity reactions is mediated by CD4 T lymphocytes, in allergic contact dermatitis it appears that CD4 T lymphocytes have the suppressor role, with CD8 T lymphocytes having the effector role. [source]

NF-,B as a potential molecular target for cancer therapy

BIOFACTORS, Issue 1 2007
Chae Hyeong Lee
Abstract Nuclear factor ,B (NF-,B), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-,B induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-,B activation which mediates resistance to chemo- and radio-therapy. Therefore, the inhibition of NF-,B activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-,B can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-,B in carcinogenesis and the therapeutic potential of targeting NF-,B in cancer therapy. [source]

Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signatures

CANCER, Issue 16 2009
Chiara Braconi MD
Abstract BACKGROUND: The presence of vascular invasion in hepatocellular cancer (HCC) correlates with prognosis, and is a critical determinant of both the therapeutic approach and the recurrence or intrahepatic metastases. The authors sought to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC. METHODS: A gene expression signature associated with vascular invasion derived from 81 human cases of HCC was used to screen a database of 453 genomic profiles associated with 164 bioactive molecules using the connectivity map. Candidate agents were identified by their inverse correlation to the query gene signature. The efficacy of the candidate agents to target invasion was experimentally verified in PLC/PRF-5 and HepG2 HCC cells. RESULTS: The gene signature associated with vascular invasion in HCC comprised of 47 up-regulated and 26 down-regulated genes. Computational bioinformatics analysis revealed several putative candidates, including resveratrol and 17-allylamino-geldanamycin (17-AAG). Both of these agents reduced HCC cell invasion at noncytotoxic concentrations. 17-AAG, a heat shock protein 90 (HSP-90) inhibitor, was shown to modulate the expression of several diverse cancer-associated genes, including ADAMTS1, part of the query signature, and maspin, an HSP-90,associated protein with a tumor suppressor role in HCC. CONCLUSIONS: Candidates for further evaluation as therapies to limit invasion in HCC have been identified using a computational bioinformatics analysis of phenotype-associated gene expression. Phenotype targeting using genomic profiling is a rational approach for drug discovery. Therapeutic strategies targeting a defined cancer-associated phenotype can be identified without a detailed knowledge of individual downstream targets. Cancer 2009. 2009 American Cancer Society. [source]