Evaluation of exercises designed to increase children's use of descriptive words.

Thesis (Ed.M.)--Boston Universit

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents

NAD(P)H Quinone Oxidoreductase Protects TAp63γ from Proteasomal Degradation and Regulates TAp63γ-Dependent Growth Arrest

BACKGROUND: p63 is a member of the p53 transcription factor family. p63 is expressed from two promoters resulting in proteins with opposite functions: the transcriptionally active TAp63 and the dominant-negative DeltaNp63. Similar to p53, the TAp63 isoforms induce cell cycle arrest and apoptosis. The DeltaNp63 isoforms are dominant-negative variants opposing the activities of p53, TAp63 and TAp73. To avoid unnecessary cell death accompanied by proper response to stress, the expression of the p53 family members must be tightly regulated. NAD(P)H quinone oxidoreductase (NQO1) has recently been shown to interact with and inhibit the degradation of p53. Due to the structural similarities between p53 and p63, we were interested in studying the ability of wild-type and polymorphic, inactive NQO1 to interact with and stabilize p63. We focused on TAp63gamma, as it is the most potent transcription activator and it is expected to have a role in tumor suppression. PRINCIPAL FINDINGS: We show that TAp63gamma can be degraded by the 20S proteasomes. Wild-type but not polymorphic, inactive NQO1 physically interacts with TAp63gamma, stabilizes it and protects it from this degradation. NQO1-mediated TAp63gamma stabilization was especially prominent under stress. Accordingly, we found that downregulation of NQO1 inhibits TAp63gamma-dependant p21 upregulation and TAp63gamma-induced growth arrest stimulated by doxorubicin. CONCLUSIONS/SIGNIFICANCE: Our report is the first to identify this new mechanism demonstrating a physical and functional relationship between NQO1 and the most potent p63 isoform, TAp63gamma. These findings appoint a direct role for NQO1 in the regulation of TAp63gamma expression, especially following stress and may therefore have clinical implications for tumor development and therapy

Theories of Procedural Justice and criteria for Fairness Judgements

Blader and Tyler (2003), following the 'Organisational Justice' school of thought, attempted to further its concern with the nature of procedural justice by proposing their 'Four Component Model of Procedural Justice'. Darcy (2005) tested three of the components by recent empirical research into the factors that impact directly on an employee's perception of fairness in relation to the termination of their employment. She found that factors derived from Blader and Tyler's model to be significant predictors of fairness judgments and in so doing confirms the relevance of the three components of Blader and Tyler's model. This paper reports briefly on Darcy's work but then turns its attention to the fourth component, formal quality of treatment. Its attempt to conceptualise it further from the perspective of recent philosophising in the traditional natural law approach

Immunocytochemical p63 expression discriminates between primary cutaneous follicle centre cell and diffuse large B-cell lymphoma-leg type, and is of the TAp63 isoform

INTRODUCTION: The p63 gene shares structural and functional homologies with the p53 family of transcriptional activators, but differs in exhibiting a consistent expression pattern in normal tissues. Although p63 is rarely mutated in malignancy studies of primary human tumours and cell lines suggest p63 may promote tumour development. In non-Hodgkin's nodal lymphoma, TAp63 expression in follicular lymphoma (54%) and diffuse large B-cell lymphoma (34%) has been described and correlated with proliferative index. In this study, we analysed a series of primary cutaneous B-cell lymphomas for immunohistochemical expression of p63. METHODS: 30 cases of diffuse large B-cell lymphoma leg type (pcDLBCLL) and 34 cases follicle centre cell lymphoma (pcFCCL) were stained using a generic antibody to p63, and a subset of these with an antibody specific for delta-Np63 isoform. RESULTS: Results indicate a significant difference between pcDLBCLL (21/30) & pcFCCL(4/34) in p63 expression (p=0.000); expression correlated strongly with proliferation rate as assessed by Ki-67 (p= 0.015). None of the p63(+) cases tested expressed delta-Np63 isoform suggesting expression is of the TAP isoform. CONCLUSION: Functional studies are required to clarify the significance of p63 overexpression in primary cutaneous B-cell lymphoma. This article is protected by copyright. All rights reserved