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Peter A Hall

Publications and source records attributed to Peter A Hall.

14 recordsLinked to original sources
PubMed2006

Altered patterns of transcription of the septin gene, SEPT9, in ovarian tumorigenesis.

Ovarian carcinoma represents the most lethal gynaecological malignancy. A variety of morphological subtypes are recognised (e.g. serous, mucinous, endometrioid), which may be benign, borderline or malignant. While their relationship is controversial, knowledge of the molecular mechanisms of ovarian tumorigenesis may help resolve this issue and perhaps identify early markers of disease. Perturbed patterns of expression of the SEPT9 gene on chromosome 17q25.3 have been implicated in a variety of tumour types including both breast and ovarian neoplasia. In preliminary studies, we showed that SEPT9 mRNA was upregulated in a bank of ovarian tumours, which included benign, borderline and malignant tumours, and reported increased levels of one splice variant, SEPT9_v4*. We now describe a comprehensive analysis of SEPT9 expression specifically in serous and mucinous ovarian tumours (benign, borderline and malignant), using cDNA microarray, semi- and quantitative RTPCR of microdissected archival tumour material. Our data show consistent and specific overexpression of both SEPT9_v1 and SEPT9_v4* transcripts in the epithelial component of ovarian tumours. These transcripts show highest levels of expression in serous and mucinous borderline tumours. SEPT9_v1 is also upregulated in both serous and mucinous carcinomas. Interestingly, highest levels of expression are observed in serous borderline and low-grade tumours rather than high-grade in keeping with a model of progression of benign, borderline and low-grade serous tumours.

Cell Transformation, Neoplastic↗
PubMed2006

Changed times at Hematological Oncology.

This editorial describes the changes to Hematological Oncology over the past 12 months and redefines the scope and the goals of the journal. As well as changes in format, an electronic manuscript submission system and a stringent peer-review policy (outlined here) have been implemented. The journal is a vehicle for high-quality articles in the broad field of experimental and clinical hematological oncology, and a medium for the publication of translational research. As well as submitted material, the journal solicits and publishes high-quality reviews from leading experts.

Hematologic Neoplasms↗
PubMed2006

Assessing p53 in clinical contexts: unlearned lessons and new perspectives.

There is compelling evidence for the central role of the p53 pathway in human neoplasia but, despite an enormous literature, the clinical utility of assessing this pathway remains ambiguous. Even simple questions about the assessment of p53 status in clinical samples remain unanswered and the literature is confusing and often contradictory. The p53 pathway is certainly complicated and the biochemical mechanisms for regulating the function of p53 and its downstream consequences are rabbinical in complexity. This perspective considers this complexity and the reasons why establishing the true utility of clinical assessment of p53 has proven to be so difficult. Indeed, recent observations regarding the existence of alternate splice variants of p53, the complexity of p53 regulation, and the existence of allelic variants of p53 and its regulators with distinct functionality makes the situation even more complex. Problems with the available assays are considered and the need to consider an array of methodological issues is emphasized. Newer strategies including analysis of the expression of downstream targets of p53 and the use of threshold strategies to measure p53 protein may provide more robust measures of the p53 pathway in clinical settings, perhaps coupled with cheap sequencing-based approaches for mutation (and polymorphism) detection. However, progress will only be made if these methodological issues are resolved and robust assays are performed in the context of appropriately powered studies in clinical trial settings.

Alleles↗
PubMed2006

Neurocognitive influences on health behavior in a community sample.

CONTEXT: Dominant models of individual health behavior omit biological variables entirely and are composed almost exclusively of social-cognitive and conative variables. Research from the neurosciences suggests a role for brain function in explaining behaviors that require active self-regulation for consistent performance. However, the association between brain function and health behavior is underexplored. OBJECTIVE: To examine the predictive power of executive function for 2 health risk behaviors and 2 health protective behaviors in healthy adults. DESIGN: A cross-sectional community sample (N = 216) of adults 20-100 years of age were administered a battery of neuropsychological tests and completed self-report questionnaires regarding their health practices. It was hypothesized that poor performance on neuropsychological tests tapping executive function would be associated with poor health behavior tendencies. RESULTS: Errors on the Stroop task were positively associated with health risk behavior and negatively associated with health protective behavior after controlling for demographics, education, and IQ. CONCLUSION: Executive function is associated with health behavior tendencies. If the association is causal, explanatory models of individual health behavior should be revised to account for individual differences in biologically imbued self-regulatory abilities.

Adult↗
PubMed2005

The septin-binding protein anillin is overexpressed in diverse human tumors.

Anillin is an actin-binding protein that can bind septins and is a component of the cytokinetic ring. We assessed the anillin expression in 7,579 human tissue samples and cell lines by DNA microarray analysis. Anillin is expressed ubiquitously but with variable levels of expression, being highest in the central nervous system. The median level of anillin mRNA expression was higher in tumors than normal tissues (median fold increase 2.58; 95% confidence intervals, 2.19-5.68, P < 0.0001) except in the central nervous system where anillin mRNA levels were lower in tumors. We developed a sensitive reverse transcription-PCR strategy to show that anillin mRNA is expressed in cell lines and in cDNA panels derived from fetal and adult tissues, thus validating the microarray data. We compared anillin with Ki67 mRNA expression and found a significant linear relationship between anillin and Ki67 mRNA expression (Spearmann r approximately 0.6, P < 0.0001). Anillin mRNA expression was analyzed during tumor progression in breast, ovarian, kidney, colorectal, hepatic, lung, endometrial, and pancreatic tumors and in all tissues there was progressive increase in anillin mRNA expression from normal to benign to malignant to metastatic disease. Finally, we used anti-anillin sera and found nuclear anillin immunoreactivity to be widespread in normal tissues, often not correlating with proliferative compartments. These data provide insight into the existence of nonproliferation-associated activities of anillin and roles in interphase nuclei. Thus, anillin is overexpressed in diverse common human tumors, but not simply as a consequence of being a proliferation marker. Anillin may have potential as a novel biomarker.

Actins↗
PubMed2005

Multimodality expression profiling shows SEPT9 to be overexpressed in a wide range of human tumours.

Septins are an evolutionarily conserved family of GTPases with diverse functions including roles in cytokinesis that have been implicated in neoplasia. To address the potential role of SEPT9 in tumorigenesis, we assessed the expression of SEPT9 in 7287 fresh frozen human tissue samples and 292 human cell lines by microarray analysis. In addition, we used a sensitive RT-PCR strategy to define the expression of SEPT9 isoforms in archival formalin-fixed and paraffin-embedded normal human tissues. The mRNA data were further confirmed by immunohistological analyses of SEPT9 protein expression in normal human tissues using antisera that detect SEPT9 isoforms. Using these complementary approaches, we demonstrate that SEPT9 mRNA and protein are expressed ubiquitously, with the isoforms showing tissue-specific expression. The microarray analysis indicates that there is consistent overexpression of SEPT9 in diverse human tumours including breast, CNS, endometrium, kidney, liver, lung, lymphoid, oesophagus, ovary, pancreas, skin, soft tissue and thyroid. Since tumours are commonly associated with enhanced cell proliferation, we examined the possible correlation of Ki67 and SEPT9 expression in normal tissues and tumours. Our data indicate that the overexpression of SEPT9 in neoplasia is not simply a proliferation-associated phenomenon, despite its role in cytokinesis.

Cell Movement↗
PubMed2005

New perspectives on neoplasia and the RNA world.

Key tenets of modern biology are the central place of protein in cell regulation and the flow of genetic information from DNA to RNA to protein. However, it is becoming increasingly apparent that genomes are much more complex than hitherto thought with remarkably complex regulatory systems. The notion that the fraction of the genome involved in coding protein is all that matters is increasingly being questioned as the roles of non-coding RNA (ncRNA) in cellular systems becomes recognised. The RNA world, including microRNA (miRNA), small inhibitory RNA (siRNA) and other RNA species, are now recognised as being crucial for the regulation of chromatin structure, gene expression, mRNA processing and splicing, mRNA stability and translational control. Furthermore such ncRNA systems may be perturbed in disease states and most notably in neoplasia, including in haematological malignancies. Here the burgeoning evidence for a role of miRNA in neoplasia is reviewed and the importance of understanding the RNA world emphasised.

Alternative Splicing↗
PubMed2005

Expression profiling the human septin gene family.

The septins are an evolutionarily conserved family of GTP-binding proteins involved in diverse processes including vesicle trafficking, apoptosis, remodelling of the cytoskeleton, infection, neurodegeneration, and neoplasia. The present paper reports a comprehensive study of septin gene expression by DNA microarray methods in 10 360 samples of normal, diseased, and tumour tissues. A novel septin, SEPT13, has been identified and is shown to be related to SEPT7. It is shown that SEPT13 and the other known human septins are expressed in all tissue types but some show high expression in lymphoid (SEPT1, 6, 9, and 12) or brain tissues (SEPT2, 3, 4, 5, 7, 8, and 11). For a given septin, some isoforms are highly expressed in the brain and others are not. For example, SEPT8_v2 and v1, 1* and 3 are highly expressed in the brain and cluster with SEPT2, 3, 4, 5, 7, and 11. However, a probe set specific for SEPT8_v1 with low brain expression clusters away from this set. Similarly, SEPT4 has lymphoid and non-lymphoid forms; SEPT2 has lymphoid and central nervous system (CNS) forms; and SEPT6 and SEPT9 are elevated in lymphoid tissues but both have forms that cluster away from the lymphoid forms. Perturbation of septin expression was widespread in disease and tumours of the various tissues examined, particularly for conditions of the CNS, where alterations in all 13 septin genes were identified. This analysis provides a comprehensive catalogue of the septin family in health and disease. It is a key step in understanding the role of septins in physiological and pathological states and provides insight into the complexity of septin biology.

Amino Acid Sequence↗
PubMed2005

SEPT9_v4 expression induces morphological change, increased motility and disturbed polarity.

Several lines of evidence indicate that altered expression of SEPT9 is seen in human neoplasia. In particular there is evidence of altered expression of the SEPT9_v4 isoform. The functional consequences of this remain unclear. We have studied the expression of wild-type- and GTP-binding mutants (G144V and S148N) of the SEPT9_v4 isoform in the MCF7 cell line as a model for its deregulation in neoplasia. We find that SEPT9_v4 expression induces dramatic actin cytoskeletal reorganization with the formation of processes around the cell periphery. Expression of the SEPT9_v4 isoform and a G144V mutant cause delocalization of endogenous SEPT9 from filamentous structures but the S148N mutant does not have this effect. In addition SEPT9_v4 isoform expression enhances cell motility and is associated with perturbation of directional movement. Expression of SEPT9_v4 GTP binding mutants also has potent effects on morphology and motility and causes loss of normal polarity, as judged by Golgi reorientation assays. The phenotypes induced by expression of the SEPT9_v4 isoform and the GTP mutants provide an insight into possible mechanisms of SEPT9_v4 function and suggest that the GTPase functions have both ras- and rab-like features. We propose a model in which overexpression of the SEPT9_v4 isoform in neoplasia is associated with perturbation of SEPT9 complexes, leading to phenotypes associated with neoplasia.

Actins↗
PubMed2005

A Strategy for defining biologically relevant levels of p53 protein expression in clinical samples with reference to endometrial neoplasia.

Numerous studies have investigated p53 immunohistochemistry as a diagnostic, prognostic or predictive marker in various neoplasms. However, the literature is confused and contradictory paying little attention to pivotal aspects of p53 biology nor basic immunohistochemical principles. Here we highlight the effect of varying antibody concentration on p53 immunohistochemical expression. Six uterine endometrioid carcinomas, one uterine serous carcinoma (USC) and a proliferative endometrium were stained with antip53 antibody D07 at varying dilutions. Cases were scored on a scale of 0-6 depending on the percentage of positive nuclei. Greater than 95% of epithelial cells in the USC were positive at all dilutions. The proliferative endometrium exhibited positive staining of >95% of epithelial cells at low dilutions but at high dilutions most epithelial cells were negative. The proportion of positive tumor nuclei in the endometrioid carcinomas varied markedly with antibody concentration. We illustrate that the signal obtained from p53 immunohistochemistry is dependent on antibody concentration. This has diverse implications. First, the p53 labeling index is unreliable without attention to such issues. Second, comparisons between studies are not valid since different antibody concentrations (and other variables) are used. Thirdly, standardization between laboratories is necessary if clinical utility is to be attached to markers including p53. We propose a strategy for determining the optimal p53 antibody concentration.

Adenocarcinoma↗
PubMed2004

Properties of SEPT9 isoforms and the requirement for GTP binding.

Members of the evolutionarily conserved septin family of genes are emerging as key components of several cellular processes including membrane trafficking, cytokinesis, and cell-cycle control events. SEPT9 has been shown to have a complex genomic architecture, such that up to 15 different isoforms are possible by the shuffling of five alternate amino termini and three alternate carboxy termini. Genomic and transcriptional alterations of SEPT9 have been associated with neoplasia. The present study has used a Sept9-specific antibody to determine the pattern of isoform expression in a range of tumour cell lines. Western blot analysis indicated considerable variation in the relative amounts and isoform content of Sept9. Immunofluorescence studies showed a range of patterns of cytoplasmic localization ranging from mainly particulate to mainly filamentous. Expression constructs were also generated for each amino terminal isoform to investigate the patterns of localization of individual isoforms and the effects on cells of ectopic expression. The present study shows that the epsilon isoform appears filamentous in this overexpression system while the remaining isoforms are particulate and cytoplasmic. Transient transfection of individual constructs into tumour cell lines results in cell-cycle perturbation with a G2/M arrest and dramatic growth suppression, which was greatest in cell lines with the lowest amounts of endogenous Sept9. Similar phenotypic observations were made with GTP-binding mutants of all five N-terminal variants of Sept9. However, dramatic differences were observed in the kinetics of accumulation of wild-type versus mutant septin protein in transfected cells. In conclusion, the present study shows that the expression patterns of Sept9 protein are very varied in a panel of tumour cell lines and the functional studies are consistent with a model of septin function as a component of a molecular scaffold that contributes to diverse cellular functions. Alterations in the levels of Sept9 protein by overexpression of individual isoforms can clearly perturb cellular behaviour and may thus provide a mechanistic explanation for observations of deranged septin expression in neoplasia.

Actins↗
PubMed2004

The pathobiology of the septin gene family.

Septins are an evolutionarily conserved group of GTP-binding and filament-forming proteins that belong to the large superclass of P-loop GTPases. While originally discovered in yeast as cell division cycle mutants with cytokinesis defects, they are now known to have diverse cellular roles which include polarity determination, cytoskeletal reorganization, membrane dynamics, vesicle trafficking, and exocytosis. Septin proteins form homo- and hetero-oligomeric polymers which can assemble into higher-order filaments. They are also known to interact with components of the cytoskeleton, ie actin and tubulin. The precise role of GTP binding is not clear but a current model suggests that it is associated with conformational changes which alter binding to other proteins. There are at least 12 human septin genes, and although information on expression patterns is limited, most undergo complex alternative splicing with some degree of tissue specificity. Nevertheless, an increasing body of data implicates the septin family in the pathogenesis of diverse disease states including neoplasia, neurodegenerative conditions, and infections. Here the known biochemical properties of mammalian septins are reviewed in the light of the data from yeast and other model organisms. The data implicating septins in human disease are considered and a model linking these data is proposed. It is posited that septins can act as regulatable scaffolds where the stoichiometry of septin associations, modifications, GTP status, and the interactions with other proteins allow the regulation of key cellular processes including polarity determination. Derangements of such septin scaffolds thus explain the role of septins in disease states.

Animals↗
PubMed2004

Detecting and quantifying apoptosis in tissue sections.

Various techniques exist for the identification of apoptosis in tissue sections or intact cells. The use of simple morphology, electron microscopy, DNA-end labeling techniques, and immunochemical methods are reviewed, with a particular emphasis on in situ end-labeling. The analysis of apoptotic cells and methods for their quantification are also discussed.

Apoptosis↗