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Biomedical subjects

M L Goodson

Publications and source records attributed to M L Goodson.

10 recordsLinked to original sources
PubMed2006

Cyclin A activity predicts clinical outcome in oral precancer and cancer.

Accurate, predictive assessment of the behaviour of oral cancers and precancers remains elusive. Increasing dysregulation of cell proliferation is a feature of carcinogenesis, and alterations in cyclin proteins regulating cell cycle progression are involved in enhanced cell proliferation. The authors of the present study have previously demonstrated increased proliferative activity in oral dysplastic lesions and poorly differentiated carcinomas, and hypothesize that cell proliferation can be used as a predictive agent in clinical management. In this preliminary study, immunohistochemical quantification of cyclin A expression was carried out for 33 excised oral lesions (ranging from mild dysplasia to invasive squamous cell carcinoma, SCC). Clinical outcome was determined as: no disease after 2 years follow-up, persistent disease, or further disease presentation. Labelling Indices (LIs) ranged from 5.5 to 32.1%, and whilst a trend to increased labelling in increasingly dysplastic and neoplastic tissue was seen, this was not statistically significant (P=0.06). High LIs were related to poor clinical outcome (P=0.003), suggesting a definite role for cyclin A measurement as a predictive tool in clinical management.

Adult↗
PubMed2004

A study of public opinion on the use of tissue samples from living subjects for clinical research.

AIMS: To assess public opinion on the use of tissue samples from living adults and children for clinical research. METHODS: A questionnaire study of 100 healthy volunteers (100% response rate) from a Newcastle NHS dental practice. The issues investigated were the types of tissues that individuals were prepared to donate for research, the type of research donors would be prepared to consent to, and attitudes to research on children's tissues. RESULTS: Eighteen per cent of the participants said that they would not give consent for research to be carried out on their tissues, 50% would not give consent for the donation of a child's tissues. Only 26% of subjects said that they would give consent for research on genetic cloning compared with 82% for cancer research. Sex differences existed in the responses. CONCLUSIONS: Greater research attention needs to be given to public opinion on the use of tissue from living subjects for medical research to facilitate drafting of new legislation.

Adult↗
PubMed2001

Regulation of heat shock transcription factor 1 by stress-induced SUMO-1 modification.

Heat shock transcription factor 1 (HSF1) mediates the induction of heat shock protein gene expression in cells exposed to elevated temperature and other stress conditions. In response to stress HSF1 acquires DNA binding ability and localizes to nuclear stress granules, but the molecular mechanisms that mediate these events are not understood. We report that HSF1 undergoes stress-induced modification at lysine 298 by the small ubiquitin-related protein called SUMO-1. Antibodies against SUMO-1 supershift the HSF1 DNA-binding complex, and modification of HSF1 in a reconstituted SUMO-1 reaction system causes conversion of HSF1 to the DNA-binding form. HSF1 colocalizes with SUMO-1 in nuclear stress granules, which is prevented by mutation of lysine 298. Mutation of lysine 298 also results in a significant decrease in stress-induced transcriptional activity of HSF1 in vivo. This work implicates SUMO-1 modification as an important modulator of HSF1 function in response to stress.

Cell Compartmentation↗
PubMed2001

Sumo-1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor.

Heat shock transcription factor 2 (HSF2) is a transcription factor that regulates heat shock protein gene expression, but the mechanisms regulating the function of this factor are unclear. Here we report that HSF2 is a substrate for modification by the ubiquitin-related protein SUMO-1 and that HSF2 colocalizes in cells with SUMO-1 in nuclear granules. Staining with anti-promyelocytic leukemia antibodies indicates that these HSF2-containing nuclear granules are PML bodies. Our results identify lysine 82 as the major site of SUMO-1 modification in HSF2, which is located in a "wing" within the DNA-binding domain of this protein. Interestingly, SUMO-1 modification of HSF2 results in conversion of this factor to the active DNA binding form. This is the first demonstration that SUMO-1 modification can directly alter the DNA binding ability of a transcription factor and reveals a new mechanism by which SUMO-1 modification can regulate protein function.

Biological Transport↗
PubMed1996

Structure of the mouse Saa4 gene and its linkage to the serum amyloid A gene family.

The serum amyloid A (SAA) proteins are a polymorphic family of apolipoproteins associated with high-density lipoproteins (HDL). Three distinct subfamilies have been identified: (i) a cytokine-induced acute phase subfamily that is hepatically produced and can become the major apolipoprotein on HDL (SAA1, SAA2); (ii) a peripherally produced acute phase SAA3 that is only a minor HDL apolipoprotein; and (iii) a constitutive subfamily (SAA4) that is a minor normal HDL apolipoprotein comprising more than 90% of the SAA during homeostasis. Here we define the structure of the Saa4 gene. Similar to other Saa family members, it has four exons and three introns. It is 4588 bp long from the transcription start site to the end of the 3'-untranslated region and is approximately 20% larger than other Saa genes. We have located Saa4 11 kb upstream from Saa3 and 5 kb downstream from Saa1, with the pseudogene approximately 1 kb from the 5' end of Saa4. Saa4 has the same orientation as most other Saa family members, with only Saa2 having an opposing orientation. These data promote our understanding of the evolution of the Saa family. They enhance our ability to develop the mouse as a transgenic and gene deletion model to advance the understanding of the function of these apolipoproteins.

Animals↗
PubMed1995

Regulated expression of heat shock factor 1 isoforms with distinct leucine zipper arrays via tissue-dependent alternative splicing.

HSF1 mediates the stress induced expression of heat shock proteins, referred to as the cellular stress response. Previous results indicated that mammalian cells express two distinct HSF1 protein isoforms, with molecular sizes of 69 kDa (HSF1-beta) and 71 kDa (HSF1-alpha). The purpose of this study was to determine the mechanism by which these two HSF1 protein isoforms are generated. Our results show that mammalian cells express two distinct HSF1 mRNA isoforms which arise via alternative splicing of the HSF1 pre-mRNA. The two HSF1 mRNA isoforms differ by a single 66 bp exon of the HSF1 gene which is spliced into the HSF1-alpha mRNA isoform but skipped in the HSF1-beta mRNA isoform. This 66 bp exon encodes a 22 amino acid sequence, whose molecular weight (2.3 kDa) matches the difference in size between the HSF1-beta and HSF1-alpha protein isoforms (69 and 71 kDa). Further analysis reveals that this extra 22 amino acid sequence, whose insertion site in the HSF1-alpha isoform is located immediately adjacent to a C-terminal leucine zipper motif (leucine zipper 4) previously shown to be involved in maintenance of HSF1 in the non-DNA-binding control form, contains an additional, previously unidentified leucine zipper motif (leucine zipper 5). Our results also show that the levels of the two HSF1 isoforms are regulated in a tissue dependent manner, with testis expressing higher levels of the HSF1-beta isoform while heart and brain express higher levels of the HSF1-alpha isoform. These results demonstrate a new mechanism by which HSF1 expression is regulated in mammalian cells and suggest a potential role for the HSF1 isoforms in mediating tissue-dependent regulation of the cellular stress response.

Alternative Splicing↗
PubMed1995

Heat-inducible DNA binding of purified heat shock transcription factor 1.

The heat-induced expression of heat shock proteins, called the cellular stress response, is mediated by heat shock transcription factor 1 (HSF1). HSF1 exists in unstressed cells in an inactive form, which is converted to the DNA binding from upon exposure of cells to elevated temperature. We have developed a protocol for isolation of the non-DNA binding form of recombinant mouse HSF1, involving expression and affinity purification of HSF1 as a fusion with the glutathione S-transferase protein in Escherichia coli, followed by specific protease cleavage to release pure HSF1 protein. We report here that the purified inactive HSF1 can be converted to the DNA binding form by heat treatment in vitro. Chemical cross-linking analysis demonstrates that this conversion is accompanied by oligomerization of HSF1 from a monomeric to a trimeric native structure, similar to that observed for HSF1 in heat-shocked cells. These results indicate that elements residing in the HSF1 polypeptide are sufficient both for maintenance of this factor in the non-DNA binding from and for its heat-induced conversion to the DNA binding form and support a role for HSF1 as the "molecular thermostat" in eukaryotic cells, which senses adverse environmental conditions and activates the cellular stress response.

Animals↗
PubMed1995

Tissue-dependent expression of heat shock factor 2 isoforms with distinct transcriptional activities.

Heat shock factor 2 (HSF2) functions as a transcriptional regulator of heat shock protein gene expression in mammalian cells undergoing processes of differentiation and development. Our previous studies demonstrated high regulated expression and unusual constitutive DNA-binding activity of the HSF2 protein in mouse testes, suggesting that HSF2 functions to regulate heat shock protein gene expression in spermatogenic cells. The purpose of this study was to test whether HSF2 regulation in testes is associated with alterations in the HSF2 polypeptide expressed in testes relative to other mouse tissues. Our results show that mouse cells express not one but two distinct HSF2 proteins and that the levels of these HSF2 isoforms are regulated in a tissue-dependent manner. The testes express predominantly the 71-kDa HSF2-alpha isoform, while the heart and brain express primarily the 69-kDa HSF2-beta isoform. These isoforms are generated by alternative splicing of HSF2 pre-mRNA, which results in the inclusion of an 18-amino-acid coding sequence in the HSF2-alpha mRNA that is skipped in the HSF2-beta mRNA. HSF2 alternative splicing is also developmentally regulated, as our results reveal a switch in expression from the HSF2-beta mRNA isoform to the HSF2-alpha isoform during testis postnatal developmental. Transfection analysis shows that the HSF2-alpha protein, the predominant isoform expressed in testis cells, is a more potent transcriptional activator than the HSF2-beta isoform. These results reveal a new mechanism for the control of HSF2 function in mammalian cells, in which regulated alternative splicing is used to modulate HSF2 transcriptional activity in a tissue-dependent manner.

Alternative Splicing↗