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Biomedical subjects

J G Jackson

Publications and source records attributed to J G Jackson.

At least 19 recordsLinked to original sources
PubMed1997

Activation of estrogen receptor-mediated gene transcription by IGF-I in human breast cancer cells.

Estrogen and IGF-I are potent mitogens for most breast cancer cell lines, and although their signaling pathways contrast, there is considerable interaction between them. Recent evidence indicating that IGF-I can alter estrogen receptor (ER) action led us to investigate whether an inhibitor of IGF-I action. IGF-binding protein-1 (IGFBP-1), could affect transcriptional activation of ER. First, we confirmed that tamoxifen (TAM) could inhibit IGF-I-mediated proliferation of MCF-7 cells. Although TAM can increase IGFBP-3 expression in MCF-7 cells, and this binding protein has been shown to be able to inhibit IGF action, TAM had no effect on IGF-I-stimulated tyrosine phosphorylation of IGF-I receptor or the downstream signaling molecule, insulin receptor substrate-1. Therefore, to confirm that IGF-I was affecting transcriptional activation of ER, we utilized a gene reporter assay using a single consensus estrogen response element (ERE-tk-luc) upstream of luciferase. As expected, estradiol (E2; 1nM) increased transcriptional activation three- to fivefold from the ERE in three ER-positive breast cancer cell lines (MCF-7, ZR-75 and T47D). A 2.5-to 4-fold increase was also seen with IGF-I (5 nM). TAM (1 microM) effectively blocked activation by E2 and IGF-I, indicating disruption of ER-mediated transcription. As expected, human recombinant IGFBP-1 (80 nM) completely inhibited IGF-I-mediated activation of ER, however, IGFBP-1 also caused a significant decrease in E2-mediated activation. We also noticed that IGF-I increased the activity of all plasmids that we cotransfected including TATA-luc, SV40-luc and pGL Basic. This effect was post-transcriptional, as it was not affected by actinomycin D (2 micrograms/ml), while we were able to completely inhibit E2-mediated transcriptional activation of ERE-tk-luc. Unlike the complete inhibition of ER-mediated transcriptional activation by actinomycin D, IGF-I-mediated transactivation was reduced by only 50%, indicating that the activation by IGF-I represented both transcriptional and post-transcriptional effects. This study confirmed that IGF-I can cause transcriptional activation of endogenous ER in human breast cancel cells, and inhibition of ER action by IGFBP-1 suggests that IGF-1 signaling may be necessary for maximal ER activation.

Breast Neoplasms↗
PubMed1996

Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features.

BACKGROUND: The insulin-like growth factor (IGF)-binding proteins (IGFBPs) regulate the actions of the IGFs by influencing interactions between the IGFs and the IGF receptors. IGFBP-3, one of the six known species of IGFBPs, is the predominant IGFBP in serum and is expressed by breast cancer cells. Compared with estrogen receptor (ER)-positive samples, ER-negative breast cancer cell lines and tumors express higher levels of IGFBP-3. Therefore, expression of IGFBP-3 may be relevant in breast cancer biology, although it is unknown whether IGFBP-3 levels correlate with other breast cancer prognostic factors besides ER status. It is also not known how different methods used to measure IGFBP-3 in breast cancer correlate. PURPOSE: We measured IGFBP-3 messenger RNA (mRNA) and protein levels in breast tumors by different methods to test how these methods compare and to investigate the relationship between IGFBP-3 and breast cancer prognostic factors. METHODS: We analyzed 40 human breast tumors and examined IGFBP-3 expression by ligand blot analysis, immunoblot analysis, immunoradiometric assay (IRMA), and ribonuclease protection assay. Another set of 40 breast tumors, selected according to ER and progesterone receptor (PR) status, S phase, and ploidy, was analyzed by IRMA. RESULTS: In 26 (65%) of 40 samples in which RNA could be isolated, IGFBP-3 mRNA levels correlated with IGFBP-3 levels measured by IRMA (two-sided; P = .0001) but not with IGFBP-3 levels measured by ligand blot or immunoblot. Protein levels were highly correlated among all protein assays. Because the IRMA was more sensitive and accurate than the ligand blot and immunoblot assays, we used IRMA to examine IGFBP-3 levels in an additional 20 primary breast tumors with poor prognostic features (ER and PR negativity, high S phase, and aneuploidy) and in 20 tumors with good prognostic factors (opposite features). IGFBP-3 levels were threefold higher in tumors with poor prognostic features (mean +/- standard deviation = 32.8 +/- 25.2 versus 11.8 +/- 9.7 ng/mg; two-sided; P = .003). CONCLUSIONS: These findings suggest that in human breast cancer, IGFBP-3 mRNA and protein levels are correlated and higher levels of IGFBP-3 are detectable in tumors with poor prognostic features. IMPLICATIONS: IGFBP-3 may be involved in the regulation of breast cancer cell growth.

Aneuploidy↗
PubMed1996

R.D. Lawrence and the formation of the Diabetic Association.

The history of the (British) Diabetic Association is bound up with the life of Dr R.D. Lawrence, its co-founder and first Chairman. Thus the story begins with a review of his early life and experience. He himself committed some memories to paper, in autobiographical context, to which he gave the title A Splendid Life, and this review draws freely on those unpublished notes, with the permission of his sons. Unfortunately, many records, letters and documents were destroyed when the flat of his secretary, the late Miss Lilian Pearce, was damaged by the 1987 hurricane storms, and later vandalized while she was in hospital. Academically brilliant, with his heart set on becoming a surgeon, Robin Lawrence was diagnosed as having diabetes in 1920, at the age of 28. The poor prognosis lead him to set up practice in Florence, where he could at least enjoy the splendours of Italian culture. His health deteriorated badly during the winter of 1922, but alerted to the introduction of insulin therapy by Dr. G.A. Harrison, he returned to King's College Hospital, London and received his first injection of insulin on 31 May 1923. Thereafter, he devoted his life to the understanding of the disease, and the welfare of those affected by it. Together with his patient, the author and scientist H.G. Wells, Robin Lawrence was responsible for the formation of the Diabetic Association, the first patient-oriented association to be established in the United Kingdom. Historical data are taken from early issues of the Diabetic Journal and minutes of meetings to which the author has been given access.

Diabetes Mellitus↗
PubMed1996

R.D. Lawrence, H.G. Wells, G.B. Shaw: a vignette.

Among the unpublished autobiographical notes of Dr R.D. Lawrence are numerous references to his contacts and friendship with the author H.G. Wells, who was to become the first President of the (British) Diabetic Association. Wells was responsible for Lawrence being called in for consultation by George Bernard Shaw, a meeting which was to have surprising consequences.

Diabetes Mellitus↗
PubMed1995

Twinning.

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Diabetes Mellitus↗
PubMed1995

Proliferation of cultured human prostate cancer cells is inhibited by insulin-like growth factor (IGF) binding protein-1: evidence for an IGF-II autocrine growth loop.

In this study, we examined the expression of insulin-like growth factor (IGF) ligands, receptors, (IGFR1, IGFR2), and binding proteins (IGFBPs) in the human prostate cancer cell line DU145, as well as its mitogenic response to the IGFs. Using RNase protection assays, we found expression of IGF-II, IGFR1, and IGFR2 but failed to detect IGF-I messenger RNA. Distinct binding protein species as well as immunoreactive IGF-II were detected in conditioned media using radioligand and immunoblotting assays. Compared with controls, treatment with exogenous IGF-I and IGF-II resulted in stimulation of monolayer and anchorage-independent growth. Recombinant human IGFBP-1, which binds IGF-II with high affinity, inhibited IGF-II-induced monolayer growth and both baseline and IGF-II-induced anchorage-independent growth in this cell line. Our data suggest IGF-II is as an autocrine growth factor in DU145 cells, and that inhibition of IGF-II-dependent growth of human prostate cancer cells may represent a new therapeutic strategy for this disease.

Blotting, Western↗
PubMed1994

Neuropsychiatric disorders, myoclonus, and dystonia in calcification of basal ganglia pathways.

Two cases of basal ganglia calcification involving the globus pallidus are presented. Both patients had cognitive dysfunction, temporal lobe-like symptoms (including amnestic state, perceptual distortions, or complex visual hallucinations), and myoclonus. Patient 1 manifested depression, auditory hallucinations, anxiety, paranoia, and postural tremor; patient 2 manifested multifocal dystonia with dystonic tremor. These cases supplement other reports of psychotic features and dementia associated with pallidal pathology. Additionally, the phenomena encountered in these cases are considered in light of recent advances in our understanding of basal ganglia functional pathways. These cases afford a potential pathophysiological window to the possible role of the globus pallidus in these neuropsychiatric conditions. In concert with other recent findings, these cases suggest specific pathway involvement in hallucinations, paranoia, depression, myoclonus, and dystonia. Further research will indicate if these pathways play a role in schizophrenia, mood disorders, and anxiety disorders.

Adult↗
PubMed1994

Detection of insulin-like growth factor binding proteins (IGFBPs) by ligand blotting in breast cancer tissues.

Eighty breast cancer specimens were examined for insulin-like growth factor binding protein (IGFBP) expression by ligand blotting. Five distinct IGFBP species were found: a doublet at 48 and 44 kDa was IGFBP-3, the 34-kDa band was IGFBP-2, and a band at 24 kDa was IGFBP-4. A 32-kDa band was compatible with the migration position reported for IGFBP-5. IGFBP-3 was inversely correlated with ER expression, while IGFBP-4 was positively correlated with both ER and PgR. IGFBP-4 was also inversely correlated with S-phase fraction. Thus, IGFBP expression correlates with other parameters of breast cancer biology and may play a role in regulating tumor growth.

Breast Neoplasms↗
PubMed1994

Case report: use of insulin-like growth factor-I gene expression to distinguish between breast and ovarian cancer.

Autocrine expression of polypeptide growth factors may be important in the growth regulation of cancer cells. Different growth factor activities have been identified in a variety of tumors. This article describes a case of malignant ascites in a patient recently treated for breast cancer. The use of growth factor mRNA expression as a factor to differentiate between breast and ovarian origins of cancer cells contained in malignant ascites was examined. Expression of insulin-like growth factor-I (IGF-I), IGF-II, and transforming growth factor alpha mRNA was examined by ribonuclease protection assay. The tumor cells expressed IGF-II and transforming growth factor alpha, but not IGF-I mRNA. This pattern of growth factor expression is compatible with a breast cancer primary of the malignant cells contained in the ascites fluid. Therefore, IGF-I mRNA expression may be useful in distinguishing between adenocarcinomas of breast or ovarian origins.

Adenocarcinoma↗
PubMed1994

Insulin-like growth factor binding protein 1 expression inhibits insulin-like growth factor I action in MCF-7 breast cancer cells.

Interactions between insulin-like growth factor I (IGF-I) and the type of I IGF receptor may be affected by high-affinity extracellular binding proteins. To date, six distinct IGF binding proteins (IGFBPs) have been identified, but their physiological roles are not well understood. For example, depending on experimental conditions, IGFBP-1 has been shown to both enhance and inhibit IGF-I mediated mitogenesis. We have previously shown that excess exogenous IGFBP-1 inhibited IGF-I mediated growth of MCF-7 cells. In this study, we examined whether or not endogenously expressed IGFBP-1 could interfere with IGF-I mediated growth of MCF-7 cells. Cells were stably transfected with an IGFBP-1 expression vector. IGFBP-1 mRNA was produced by the cells, and protein was detected in the conditioned media by ligand blot and immunoblot. Type I IGF receptor could not be phosphorylated by IGF-I in cells expressing IGFBP-1; however, an IGF-I analogue (Arg-3-IGF-I), which cannot complex with IGFBPs, stimulated receptor phosphorylation. IGF-I did not stimulate cell growth in IGFBP-1 expressing cells. These results suggest that IGFBP-1 expression in MCF-7 breast cancer cells inhibits IGF-I induced growth by interrupting the interaction between IGF-I and its receptor.

Breast Neoplasms↗
PubMed1993

Expression of insulin-like growth factor binding proteins in human breast cancer correlates with estrogen receptor status.

The insulin-like growth factors (IGFs) have been implicated in the growth regulation of human breast cancer. Since the IGFs are associated with specific binding proteins (IGFBPs) which may modulate receptor/ligand interactions, production of IGFBPs by breast cancer cells could alter their IGF-dependent growth. This study examined the expression of IGFBPs 4, 5, and 6 in eight breast cancer cell lines (BCCLs) using ribonuclease (RNase) protection assays. IGFBP-4 mRNA was detected in all BCCLs studied. IGFBP-5 expression was higher in estrogen receptor (ER) positive cells, while IGFBP-6 mRNA was detected in only two ER negative BCCLs. We also found that E2 treatment enhanced the expression of IGFBPs 2, 4, and 5 in T47-D cells. We next studied IGFBP mRNA expression in 40 primary breast tumors. All tumors expressed mRNA for IGFBPs 2-6 but none expressed IGFBP-1 message. IGFBP-3 expression was higher in ER negative tumors, while that of IGFBP-4 and -5 was higher in ER positive specimens. These differences were statistically significant (P < .05). Ligand blot analysis of tumor extracts confirmed the presence of IGFBPs in breast cancer tissues. Thus, differential IGFBP expression in ER positive and negative tumors suggests an important role for this protein in breast cancer biology.

Blotting, Western↗
PubMed1993

Recombinant insulin-like growth factor binding protein-1 inhibits IGF-I, serum, and estrogen-dependent growth of MCF-7 human breast cancer cells.

The insulin-like growth factors (IGFs) are potent mitogens for breast cancer cells and their activity is modulated by high affinity binding proteins (IGFBPs). We have recently shown that IGFBP-1 purified from human amniotic fluid neutralizes IGF-I-dependent growth of MCF-7 cells. In this study we examined the effects of recombinant IGFBP-1 (rBP-1) on IGF-I, estradiol (E2), and serum-induced monolayer and anchorage independent growth (AIG) of MCF-7 cells. Under serum-free conditions, rBP-1 had no effect on MCF-7 basal monolayer growth. However, 40 nM rBP-1 completely blocked the mitogenic action of both IGF-I and 5% charcoal stripped serum (CSS). This concentration of rBP-1 partially inhibited E2-induced growth, while 80 nM rBP-1 completely abolished E2 mitogenicity. The addition of either excess IGF-I or 5 nM [Arg3]IGF-I, a species that does not bind IGFBPs, neutralized rBP-1 inhibitory effects. In AIG assays, 80 nM rBP-1 reduced colony number by at least 70% and decreased colony size in all treatment groups compared to control. We examined rBP-1 effects on both IGF-I binding to MCF-7 membranes and activation of type I IGF receptor (IGFR1) and found that 80 nM rBP-1 reduced IGF-I receptor binding to levels of nonspecific binding and completely abolished ligand-dependent IGFR1 phosphorylation. However, neither treatment with 5% CSS nor exposure to E2 resulted in IGFR1 phosphorylation suggesting that different mechanism(s) are responsible for rBP-1 inhibitory action under this condition. Our data suggest rBP-1 may serve as an antagonist of human breast cancer growth by interfering with growth factor-mediated cell proliferation.

Analysis of Variance↗
PubMed1993

Regulation of insulin-like growth factor binding proteins in ovarian cancer cells by oestrogen.

Insulin-like growth factor-I (IGF-I), its receptor and its binding proteins are expressed by ovarian cancer cells. In this study, we examined oestradiol (E2) regulation of IGF-I and IGF binding proteins (IGFBP) in an oestrogen-responsive ovarian cancer cell line, PE04. In serum-free conditions, PE04 cell monolayer growth was increased 1.64-fold by 3 nmol/l E2 compared with controls, although IGF-I mRNA levels were not increased. In contrast to IGF-I mRNA, IGFBP mRNA was regulated by E2. E2 caused a marked decrease in IGFBP-3 RNA, but IGFBP-2, -4 and -6 levels were only minimally depressed. IGFBP-5 mRNA levels were increased by E2. Tamoxifen had less effect on IGFBP mRNA regulation. Ligand blotting showed that E2 reduced IGFBP levels in conditioned media. IGFBP RNA was also detected in human ovarian tissue samples. Thus, IGFBP expression can be regulated in oestrogen-responsive ovarian cancer by E2.

Blotting, Western↗
PubMed1992

Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action.

BACKGROUND: The insulin-like growth factors (IGFs) play an important role in normal growth and development. Evidence suggests they may also regulate the growth of several cancer cell types. This regulation is mediated by interactions between the receptors and ligands. There is now ample evidence to suggest that these interactions are also influenced by extracellular IGF-binding proteins (IGFBPs). Six different IGFBPs have been cloned. Some species may act to inhibit the mitogenic effects of the IGFs. Since breast cancer cells are responsive to the IGFs, it is possible that regulated expression of the IGFBPs affects tumor growth. Furthermore, inhibitory binding proteins could be used as neutralizers of IGF action. PURPOSE: We conducted this study to fully characterize the expression and hormonal regulation of IGF-binding protein expression in human MCF-7 breast cancer cells and to test the ability of purified IGFBP-1 to inhibit IGF-I action. METHODS: We used ribonuclease protection assays and Western ligand blotting to examine IGFBP expression in MCF-7 cells. The effect of IGF-I, IGFBP-1, and 17 beta-estradiol on serum-free cell growth was also studied. RESULTS: MCF-7 cells expressed IGFBP-2, IGFBP-4, and IGFBP-5 RNA and protein. These cells are dependent on estrogen for growth. In short-term culture, IGF-I can substitute for estrogen. Concomitant addition of IGF-I and estrogen enhanced stimulation above the level achieved by either factor alone. Estrogen also increased IGFBP production, making it unlikely that the IGFBPs induced by estrogen in MCF-7 cells could function as major inhibitors of IGF action. In contrast, exogenous addition of IGFBP-1 could block IGF-I-induced mitogenesis; this effect was reversible by excess IGF-I. CONCLUSIONS: The studies suggest that cancer cell growth may be regulated by endogenous IGFBP expression. Furthermore, the exogenous addition of the IGFBP-1 blocked IGF-I action and potentially could be used as a pharmacologic inhibitor of IGF action.

Blotting, Western↗
PubMed1990

Renal oncocytoma: report of a case with bilateral multifocal oncocytomas.

Renal oncocytomas are uncommon, benign tumors that classically are treated by local excision or heminephrectomy. Preoperative differentiation from renal cell carcinoma is invaluable in the planning of treatment. Cases of renal oncocytoma treated conservatively have been reported. This is a case report of bilateral multifocal renal oncocytomas of which only three previous cases have been reported. Diagnosis was made from multiple fine needle biopsies and present treatment consists only of conservative observation.

Adenoma↗
PubMed1990

EASD growing pains.

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Diabetes Mellitus↗