Biomedical subjects

T Nickerson

Publications and source records attributed to T Nickerson.

11 recordsLinked to original sources

PubMed2004

The DNA sequence and comparative analysis of human chromosome 10.

The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

Animals↗

PubMed2004

The DNA sequence and analysis of human chromosome 13.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Chromosome Mapping↗

PubMed2001

In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR).

Androgen deprivation therapies for metastatic prostate cancer are useful initially, but progression to androgen independence usually results in relapse within 2 years. The molecular mechanisms underlying the clinically important transition from androgen dependence to androgen independence are poorly described. Several lines of investigation have suggested that insulin-like growth factors (IGFs) are involved in the biology of prostate cancer, but little is known about their relevance to progression to androgen independence. We used three in vivo models of androgen-dependent (AD) human prostate cancer to study this issue. Progression to androgen-independent (AI) growth was associated with a 60-fold increase in expression of IGF-I mRNA in LAPC-9 xenografts and a 28-fold increase in IGF-I expression in LNCAP xenografts, relative to the initial AD neoplasms. IGF type I receptor (IGF-IR) mRNA levels were approximately 2.5-fold and approximately 5-fold higher, respectively, in AI LAPC-9 and LNCaP tumors compared with the original AD neoplasms. AI growth of these xenografts was also associated with significant reductions in IGF binding protein-3 expression. LAPC-4 xenografts, which previously have been shown to exhibit molecular pathology related to HER-2/neu expression with progression to AI, showed relatively minor changes in expression of the genes investigated, but we nevertheless found evidence of increased IGF-IR phosphorylation with progression to androgen independence in this model. Taken together with prior observations, our results suggest that deregulation of expression of genes related to any one of several critical receptor tyrosine kinase regulatory systems, including IGF signaling, may confer androgen independence.

Androgens↗

PubMed1999

Castration-induced apoptosis of androgen-dependent shionogi carcinoma is associated with increased expression of genes encoding insulin-like growth factor-binding proteins.

Insulin-like growth factor (IGF)-I has well-characterized mitogenic and antiapoptotic effects that are essential for maintenance of the normal prostate and may be important during regression of the normal prostate and/or prostate tumors induced by androgen-targeting therapies for prostate cancer. IGF-I activity is modulated by IGF-binding proteins (IGFBPs). Here we examine IGFBP expression during regression of androgen-dependent Shionogi carcinoma tumors after castration. In this model, we observe a 90% reduction in Shionogi tumors by 10 days postcastration. Northern blotting of RNA from tumors collected at various times after castration indicates a rapid induction of IGFBP-5 concomitant with apoptotic regression of tumors, as detected by Apoptag staining of tumor sections after castration. IGFBP-5 mRNA was not detectable in tumors from control animals, but levels increased 120-fold in tumors 3 days after castration. The mRNAs for IGFBP-3 and 4 were abundant in Shionogi tumors from intact mice and decreased to -33% and -20% of control, respectively. Castration had no significant effect on IGFBP-2 expression. Treatment with calcium channel blockers inhibited castration-induced apoptosis and tumor regression and also significantly inhibited up-regulation of IGFBP-5 after castration. These data provide strong evidence for a functional role of IGFBP-5 expression in mediating the apoptosis induced by androgen deprivation in androgen-dependent neoplasia.

Amlodipine↗

PubMed1999

Bicalutamide (Casodex)-induced prostate regression involves increased expression of genes encoding insulin-like growth factor binding proteins.

OBJECTIVES: To examine the effects of bicalutamide (Casodex), a pure antiandrogen with high specificity for the androgen receptor, on insulin-like growth factor binding protein (IGFBP) expression and apoptotic regression of the rat ventral prostate. METHODS: Rats were treated daily with 10 mg/kg body weight bicalutamide or vehicle alone. Ventral prostates were collected at various days of treatment. Northern blot analysis was performed to quantitate expression of genes encoding IGFBPs, and the TUNEL method was used to determine the extent of apoptosis in ventral prostate. RESULTS: In rats treated daily with bicalutamide, increases in mRNA levels of IGFBP-2, -3, -4, and -5 were detectable by Northern blotting by 6 hours and reached 6 to 10-fold of control levels after 5 days of treatment. The time-course of induction of apoptosis in the ventral prostate by bicalutamide, as detected in situ by the TUNEL method, corresponded to the time-course of induction of IGFBP expression. CONCLUSIONS: We demonstrate that apoptotic regression of the ventral prostate during bicalutamide treatment is accompanied by increased expression of IGFBP-2, -3, -4, and -5. Rapid induction of IGFBPs, which can limit access of insulin-like growth factors (IGFs) to the IGF-I receptor, may play a role in the induction of apoptosis by antiandrogens, particularly in view of the increasing evidence that IGF-I inhibits apoptosis. These results document a previously unrecognized effect of antiandrogens and extend our previous studies relating IGF physiology to prostate biology. Together with evidence that a strong positive correlation exists between plasma IGF-I levels and prostate cancer risk, our data suggest that IGF physiology may play a key role in prostate cancer biology and is strongly influenced by androgen-targeting therapies.

Androgen Antagonists↗

PubMed1999

Vitamin D analogue EB1089-induced prostate regression is associated with increased gene expression of insulin-like growth factor binding proteins.

Vitamin D analogues have an antiproliferative effect on prostate cancer cells in vitro and thus have been proposed as candidates for chemoprevention of prostate cancer. Insulin-like growth factor (IGF)-I has been shown to protect cells from apoptosis and plays an essential role in normal prostate physiology. We have studied the effects of the 1,25-dihydroxyvitamin D3 analogue EB1089 on the IGF system in the prostate in vivo. Treatment of rats with EB1089 for 14 days caused a 25% decrease in ventral prostate weight. Apoptosis was detected in prostate sections of EB1089-treated rats by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL) assay and histologic examination of hematoxylin/eosin stained tissue sections indicated that secretory epithelial cells were flattened, a characteristic of cells undergoing pressure-induced atrophy. Ventral prostate regression was associated with 15- to 25-fold increases in gene expression of IGF-binding proteins (IGFBPs)-2,-3,-4 and -5. We also observed a 40-fold increase in prostatic IGF-I mRNA levels in response to EB1089. Although we have previously shown that castration of rats leads to upregulation of IGFBPs in the ventral prostate, EB1089 treatment had no effect on serum levels of dihydrotestosterone or free testosterone. These results suggest that prostate regression induced by EB1089 may be related to alterations in availability of IGF-I as a result of increased production of IGFBPs.

Animals↗

PubMed1999

Regression of DMBA-induced breast carcinoma following ovariectomy is associated with increased expression of genes encoding insulin-like growth factor binding proteins.

Insulin-like growth factor I (IGF-I) has well characterized mitogenic and antiapoptotic effects in both normal and neoplastic mammary epithelial cells which are mediated through the IGF-I receptor. IGF activity is modulated by a family of high affinity IGF binding proteins (IGFBPs 1-6). Here we show that gene expression of IGFBP-2, -3, -4 and -5 increases rapidly in DMBA-induced rat mammary tumors following ovariectomy. We observed a 90% reduction in volume of DMBA-induced rat mammary tumors by 14 days post-ovariectomy. The time course of maximal tumor regression was associated with increased gene expression of IGFBPs, as detected by Northern blot analysis. IGFBP-2, -3, -4 and -5 mRNA levels increased from 2- to 16-fold of control by 14 days of estrogen-ablation. These results are compatible with the hypothesis that response of DMBA-induced mammary tumors to estrogen deprivation therapies involves reduction of IGF bioactivity secondary to upregulation of expression of IGF binding proteins.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1998

Castration-induced apoptosis in the rat ventral prostate is associated with increased expression of genes encoding insulin-like growth factor binding proteins 2,3,4 and 5.

Insulin-like growth factor binding proteins (IGFBPs) have recently been demonstrated to act as regulators of apoptosis in vitro in both prostate and breast cancer cell lines. We show here that gene expression of IGFBP-2,-3,-4 and -5 increase rapidly in the rat ventral prostate following castration. Increases in IGFBP mRNA levels were detectable by Northern blotting by 6 hours and reached 5 to 10 fold of control levels at 72 hours after castration. Apoptosis in the ventral prostate, as detected in situ by the TUNEL method, was also induced as early as 6 hours after castration. TRPM-2/clusterin, a gene known to be associated with involution of the prostate, was not detected in sham castrated controls but was expressed by 24 hours following androgen ablation. IGF-I mRNA levels increased to 160% of control values within 6 hours following castration, then decreased gradually over the next 72 hours to 35% of control. Affinity labelling experiments demonstrated that IGF-I receptor levels increased initially after castration with peak binding at 24 hours, then declined to levels lower than control. These results suggest that rapid induction of IGFBPs in the rat ventral prostate following androgen ablation may play a role in apoptosis and involution of the prostate gland.

Animals↗

PubMed1997

Insulin-like growth factor binding protein-3 induces apoptosis in MCF7 breast cancer cells.

Insulin-like growth factors (IGFs) are known to have potent antiapoptotic activity. The antiestrogen ICI 182,780 (ICI) is a potent inhibitor of MCF7 human breast cancer cell growth and has recently been reported to act as an antiproliferative agent in part via upregulation of expression of insulin-like growth factor binding proteins (IGFBPs) -3 and -5, which attenuate the bioactivity of IGFs in many experimental systems. We show here that ICI and IGFBP-3 induce apoptosis in MCF7 cells. Treatment of MCF7 cells with 10 nM ICI or 36 nM recombinant human IGFBP. 3 for 72 hours increased apoptosis approximately 3.5-fold relative to control as quantitated by a cell death ELISA which measures DNA fragmentation. Long R3 IGF-I, an IGF-I analogue with greatly reduced affinity for IGFBPs yet similar affinity for IGF-I receptors, was a more potent inhibitor of IGFBP-3-induced and ICI-induced apoptosis than IGF-I. These results suggest that IGFBP-3 enhances apoptosis by reducing bioavailability of ligands for the IGF-I receptor and suggest that modulation of IGFBP-3 expression by ICI contributes to apoptosis induced by this compound. More generally, the data suggest that IGFBPs are regulators of apoptosis.

Antineoplastic Agents↗

PubMed1996

Regulation of insulin-like growth factor I receptor expression by the pure antiestrogen ICI 182780.

Insulin-like growth factor I (IGF-I) is a mitogen for human breast cancer cells both in vivo and in vitro. We demonstrate here that the antiestrogen ICI 182780 (ICI) at 10(-8) m decreases IGF-I receptor (IGF-IR) mRNA levels by 70% after treatment for 48 h. Measurements of mRNA stability indicate that the half-life of IGF-IR mRNA is approximately 3 h. Estradiol treatment increases the half-life of the IGF-IR mRNA to approximately 6 h and the level of IGF-IR gene transcription by 1.8-fold, whereas ICI treatment not only decreases the IGF-IR transcription rate by 50% but also decreases the IGF-IR mRNA half-life to less than 3 h. Affinity labeling studies with [125I]-IGF-I show 35% increased labeled IGF-I to MCF-7 cell membrane following estradiol treatment and 40% decreased labeling following ICI treatment. We also demonstrate that ICI attenuates IGF-I-stimulated growth. Our data suggest that attenuation of IGF-I responsivity by ICI may be due in part to reducing the IGF-IR expression.

Breast Neoplasms↗

PubMedDate not supplied

The DNA sequence and comparative analysis of human chromosome 20.

The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

Animals↗