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Biomedical subjects

Scott Powers

Publications and source records attributed to Scott Powers.

15 recordsLinked to original sources
PubMed2006

Identification of alterations in DNA copy number in host stromal cells during tumor progression.

The interactions between cancer cells and the surrounding host stromal tissue play a critical role in tumor progression and metastasis, but the molecular nature of this relationship remains largely uncharacterized. Furthermore, although genetic changes of neoplastic cells in tumors contribute significantly to tumor progression, it is not known whether similar changes occur in the adjacent host stromal microenvironment and whether they contribute to or inhibit tumorigenesis. To address this question in an unbiased and genome-wide manner, we applied high-resolution DNA copy number analysis to murine stromal DNA isolated from human xenograft tumors that were formed in immunodeficient mice. We show that numerous amplifications and deletions are found within the host stromal microenvironment, suggesting that alterations in host DNA copy number can occur and may play a significant role in modifying tumor-stromal interactions.

Animals↗
PubMed2006

Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.

The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Tension-type headache in the young.

Headache is common in childhood; recurrent headaches include both migraine and tension-type headache (TTH). Although much of the attention recently has been focused on migraine, TTH can also be problematic for children and needs further study. Standardized criteria have been developed and used for epidemiology and treatment studies, but they are yet to be validated for children. The pathophysiology, selective treatment, impact, and outcome of TTH in children need to be studied further.

Age Factors↗
PubMed2006

Rocuronium exacerbates mechanical ventilation-induced diaphragm dysfunction in rats.

OBJECTIVE: Nondepolarizing neuromuscular blocking agents are commonly used in the intensive care setting, but they have occasionally been associated with development of myopathy. In addition, diaphragmatic atrophy and a reduction in diaphragmatic force were reported after short-term controlled mechanical ventilation in animal models. We hypothesized that infusion of rocuronium, an aminosteroidal neuromuscular blocking agent, during 24 hrs of controlled mechanical ventilation would further alter diaphragm function and would enhance activation of the ubiquitin- proteasome pathway. DESIGN: Randomized, controlled experiment. SETTING: Basic animal science laboratory. SUBJECTS: Male Wistar rats, 14 wks old. INTERVENTIONS: Rats were divided into four groups: a control group, a group of anesthetized rats breathing spontaneously for 24 hrs, and two groups submitted to mechanical ventilation for 24 hrs, receiving a continuous infusion of either 0.9% NaCl or rocuronium. MEASUREMENTS AND MAIN RESULTS: In vitro diaphragm force was decreased more significantly after 24 hrs of mechanical ventilation combined with rocuronium infusion than after mechanical ventilation alone (e.g., tetanic force, -27%; p < .001 vs. mechanical ventilation). Similarly, the decrease in diaphragm type IIx/b fiber dimensions was more pronounced after mechanical ventilation with rocuronium treatment than with saline treatment (-38% and -29%, respectively; p < .001 vs. control). Diaphragm hydroperoxide levels increased similarly in both mechanically ventilated groups. Diaphragm muscle RING-finger protein-1 (MURF-1) messenger RNA expression, an E3 ligase of the ubiquitin-proteasome pathway, increased after mechanical ventilation (+212%, p < .001 vs. control) and increased further with combination of rocuronium (+320%, p < .001 vs. control). Significant correlations were found between expression of MURF-1 messenger RNA, diaphragm force, and type IIx/b fiber dimensions. CONCLUSIONS: Infusion of rocuronium during controlled mechanical ventilation leads to further deterioration of diaphragm function, additional atrophy of type IIx/b fibers, and an increase in MURF-1 messenger RNA in the diaphragm, which suggests an activation of the ubiquitin-proteasome pathway. These findings could be important with regard to weaning failure in patients receiving this drug for prolonged periods in the intensive care unit setting.

Androstanols↗
PubMed2005

Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1.

Metastasis of primary tumors leads to a very poor prognosis for patients suffering from cancer. Although it is well established that not every tumor will eventually metastasize, it is less clear whether primary tumors acquire genetic alterations in a stochastic process at a late stage, which make them invasive, or whether genetic alterations acquired early in the process of tumor development drive primary tumor growth and determine whether this tumor is going to be metastatic. To address this issue, we tested genes identified in a large-scale comparative genomic hybridization analysis of primary tumor for their ability to confer metastatic properties on a cancer cell. We identified amplification of the ACK1 gene in primary tumors, which correlates with poor prognosis. We further show that overexpression of Ack1 in cancer cell lines can increase the invasive phenotype of these cells both in vitro and in vivo and leads to increased mortality in a mouse model of metastasis. Biochemical studies show that Ack1 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac. Taken together, this study supports a theory from Bernards and Weinberg [Bernards, R. & Weinberg, R. A. (2002) Nature 418, 823], which postulates that the tendency to metastasize is largely predetermined.

Animals↗
PubMed2005

A microRNA polycistron as a potential human oncogene.

To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas. Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development in a mouse B-cell lymphoma model. Tumours derived from haematopoietic stem cells expressing a subset of the mir-17-92 cluster and c-myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-myc-induced lymphomas. Together, these studies indicate that non-coding RNAs, specifically microRNAs, can modulate tumour formation, and implicate the mir-17-92 cluster as a potential human oncogene.

Animals↗
PubMed2005

Exercise training provides cardioprotection against ischemia-reperfusion induced apoptosis in young and old animals.

Endurance exercise provides cardioprotection against ischemia-reperfusion (IR)-induced necrotic cell death in young animals. However, whether exercise-induced cardioprotection prevents IR-induced apoptosis in young and old animals is unknown. We tested the hypothesis that endurance exercise training will attenuate IR-induced myocardial apoptosis in young (4 months) and old (24 months) male F344 rats. Young and old rats remained sedentary or performed multiple bouts of moderate intensity running exercise. To induce apoptosis, isolated working hearts were exposed to 45 min of ischemia followed by 90 min of reperfusion. Assessment of myocardial levels of caspase-3 cleaved alpha-spectrin and TUNEL labeled nuclei revealed that IR resulted in apoptosis in hearts from both young and old animals. Importantly, independent of age, exercise attenuated the IR-induced apoptosis of cardiac myocytes. Moreover, exercise attenuated IR-induced calpain activation in the hearts of both young and old animals. These experiments for the first time demonstrate that exercise attenuates IR-induced myocardial apoptosis in both young and old animals. Potential mechanisms for this exercise-induced cardioprotection against IR-induced apoptosis include improved myocardial antioxidant capacity and prevention of calpain and caspase-3 activation.

Aging↗
PubMed2004

G protein-coupled receptors GPR4 and TDAG8 are oncogenic and overexpressed in human cancers.

The GPR4 subfamily consists of four G protein-coupled receptors that share significant sequence homology. In addition to GPR4, this subfamily includes OGR1, TDAG8 and G2A. G2A has previously been shown to be a potent transforming oncogene for murine 3T3 cells. Here we show that GPR4 also malignantly transforms NIH3T3 cells and that TDAG8 malignantly transforms the normal mammary epithelial cell line NMuMG. Overexpression of GPR4 or TDAG8 in HEK293 cells led to transcriptional activation from SRE- and CRE-driven promoters, independent of exogenously added ligand. TDAG8 and GPR4 are also overexpressed in a range of human cancer tissues. Our results suggest that GPR4 and TDAG8 overexpression in human tumors plays a role in driving or maintaining tumor formation.

3T3 Cells↗
PubMed2004

Wip1-deficient mice are resistant to common cancer genes.

PPM1D encodes WIP1, a serine-threonine phosphatase that had previously been shown to be the driver oncogene of a 17q23 amplicon that is present in approximately 15% of human breast tumors. However, it is unknown whether it has any role in the remaining 85% of breast tumors. A recent study using Wip1-deficient mice revealed that blocking its function significantly impaired RAS and ERBB2-induced breast tumor formation, suggesting that the inhibition of Wip1 could be a broad-spectrum treatment for breast cancer. However, because of the structure of Wip1, the development of small molecule inhibitors is a significant challenge.

Animals↗
PubMed2003

Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation.

We have developed a methodology we call ROMA (representational oligonucleotide microarray analysis), for the detection of the genomic aberrations in cancer and normal humans. By arraying oligonucleotide probes designed from the human genome sequence, and hybridizing with "representations" from cancer and normal cells, we detect regions of the genome with altered "copy number." We achieve an average resolution of 30 kb throughout the genome, and resolutions as high as a probe every 15 kb are practical. We illustrate the characteristics of probes on the array and accuracy of measurements obtained using ROMA. Using this methodology, we identify variation between cancer and normal genomes, as well as between normal human genomes. In cancer genomes, we readily detect amplifications and large and small homozygous and hemizygous deletions. Between normal human genomes, we frequently detect large (100 kb to 1 Mb) deletions or duplications. Many of these changes encompass known genes. ROMA will assist in the discovery of genes and markers important in cancer, and the discovery of loci that may be important in inherited predispositions to disease.

Aneuploidy↗
PubMed2003

Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function.

TASK3 gene (Kcnk9) is amplified and overexpressed in several types of human carcinomas. In this report, we demonstrate that a point mutation (G95E) within the consensus K+ filter of TASK3 not only abolished TASK3 potassium channel activity but also abrogated its oncogenic functions, including proliferation in low serum, resistance to apoptosis, and promotion of tumor growth. Furthermore, we provide evidence that TASK3G95E is a dominant-negative mutation, because coexpression of the wild-type and the mutant TASK3 resulted in inhibition of K+ current of wild-type TASK3 and its tumorigenicity in nude mice. These results establish a direct link between the potassium channel activity of TASK3 and its oncogenic functions and imply that blockers for this potassium channel may have therapeutic potential for the treatment of cancers.

Animals↗
PubMed2003

Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene.

Representational difference analysis (RDA) of human breast cancer was used to discover a novel amplicon located at chromosomal region 8q24.3. We examined a series of breast cancer samples harboring amplification of this region and determined that KCNK9 is the sole overexpressed gene within the amplification epicenter. KCNK9 encodes a potassium channel that is amplified from 3-fold to 10-fold in 10% of breast tumors and overexpressed from 5-fold to over 100-fold in 44% of breast tumors. Overexpression of KCNK9 in cell lines promotes tumor formation and confers resistance to both hypoxia and serum deprivation, suggesting that its amplification and overexpression plays a physiologically important role in human breast cancer.

Animals↗
PubMed2002

PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer.

We used cDNA-based genomic microarrays to examine DNA copy number changes in a panel of prostate tumors and found a previously undescribed amplicon on chromosome 17 containing a novel overexpressed gene that we termed prostate cancer gene 17 (PRC17). When overexpressed in 3T3 mouse fibroblast cells, PRC17 induced growth in low serum, loss of contact inhibition, and tumor formation in nude mice. The PRC17 gene product contains a GTPase-activating protein (GAP) catalytic core motif found in various Rab/Ypt GAPs, including RN-Tre. Similar to RN-Tre, we found that PRC17 protein interacts directly with Rab5 and stimulates its GTP hydrolysis. Point mutations that alter conserved amino acid residues within the PRC17 GAP domain abolished its transforming abilities, suggesting that GAP activity is essential for its oncogenic function. Whereas PRC17 is amplified in 15% of prostate cancers, it is highly overexpressed in approximately one-half of metastatic prostate tumors. The potent oncogenic activity of PRC17 is likely to influence the tumorigenic phenotype of these prostate cancers.

3T3 Cells↗
PubMed2002

Increased antioxidant capacity does not attenuate muscle atrophy caused by unweighting.

Previous studies have increased antioxidant capacity in skeletal muscle to attenuate oxidative stress and muscle atrophy during limb immobilization (Appell HJ, Duarte JAR, and Soares JMC. Int J Sports Med 18: 157-160, 1997; Kondo H, Miura M, Nakagaki I, Sasaki S, and Itokawa Y. Am J Physiol Endocrinol Metab 262: E583-E590, 1992). The purpose of this study was to determine the level of oxidative stress in muscle during hindlimb unweighting (HLU) and whether antioxidant supplementation can attenuate the atrophy and changes in contractile properties resulting from 14 days of unweighting. Muscle unweighting caused a 44% decrease in soleus (Sol) and a 30% decrease in gastrocnemius (GS) mass, a 7% decrease in body weight, and 28% decrease in tetanic force in the GS. Protein carbonyls increased by 44% in the Sol with HLU. Antioxidant supplementation did not attenuate the GS or Sol atrophy or the decrease in GS force generation during HLU. Sol and GS protein concentration was not different between groups. The GS was also subjected to three different oxidative challenges to determine whether the supplement increased the antioxidant capacity of the muscle. In all cases, muscles exhibited an increased antioxidant capacity. These data indicate that antioxidant supplementation was not an effective countermeasure to the atrophy associated with HLU.

Animal Feed↗