| Epigenetic Characterization of Ovarian Cancer |
Dec-2008 |
105 pages |
| Authors:
Susan K Murphy; DUKE UNIV MEDICAL CENTER DURHAM NC
|
 | The overall objective of this research was to identify genes that are aberrantly methylated in epithelial ovarian cancer. Our approach was to treat or mock treat primary normal or tumor cultured cells with drugs that inhibit DNA methyltransferase activity and then perform microarray analysis to identify genes that are likely to exhibit methylation-mediated silencing. We also employed similar analysis of 43 ovarian cell lines. Two major criteria identified genes likely ... |
|
| Influence of Snail on Integrin Beta l Expression/Activity in Breast Carcinoma |
Sep-2008 |
29 pages |
| Authors:
Robin E Bachelder; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| We provide the first evidence that Snail-1, a tumor progression factor[1-3], influences breast tumor cell adhesion to matrix proteins. Specifically, we show that Snail-1 reduces alpha2 beta1 integrin expression levels in breast tumor cells. This novel Snail-1 activity results in impaired tumor cell adhesion to the alpha2 beta1 integrin-binding matrix protein Collagen-1. As a specificity control, we show that Snail-1 does not influence alpha5 beta1 integrin levels or alpha5 beta1 ... |
|
| Early Detection of Breast Cancer via Multi-plane Correlation Breast Imaging |
Apr-2008 |
43 pages |
| Authors:
Amarpreet S Chawla; Ehsan Samel; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| One major deficiency of standard mammography is the camouflaging effect of overlapping structures in the projection images that limits the rendering of breast cancer. To minimize this effect, we proposed Multi-plane Correlation Imaging (MCI) technique. In this technique, multiple radiographic images of the breast are obtained from different angles. Angular information is used to identify and positively reinforce the lesion signals between different projections. In this phase of the study, ... |
|
| Enhancement of Anti-Telomerase Immunity Against Prostate Cancer |
01-Nov-2007 |
48 pages |
| Authors:
Johannes Vieweg; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The major objective of this proposal is to enhance the efficacy of specific active immunotherapy (SAI) by selectively eliminating or reducing CD4+ regulatory T cells (T(sub reg))1 in patients with metastatic prostate cancer. Preclinical and clinical data from our laboratory have shown that CD4+ and CD25+ co-expressing T(sub reg) play an important role in the suppression of T cell responses in the cancer patient. Moreover, we have demonstrated that elimination ... |
|
| Biological Basis for Chemoprevention of Ovarian Cancer. Addendum |
OCT 2007 |
35 pages |
| Authors:
Andrew Berchuck; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| To better understanding the etiology of ovarian cancer, we have initiated a case-control study that considers genetic susceptibility, epidemiologic factors and somatic alterations. Subjects are interviewed in their homes and 1,100 cases and 1,000 controls have been accrued. Blood and cancer samples have been collected and molecular analyses of genetic polymorphisms have been performed. We have performed an Illumina array experiment with 1,536 haplotype tagging single nucleotide polymorphisms in about ... |
|
| A Computer-Aided Diagnosis System for Breast Cancer Combining Mammography and Proteomics |
MAY 2007 |
85 pages |
| Authors:
Jonathan Jesneck; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| This study investigated a computer-aided diagnosis system for breast cancer by combining the following three data sources: mammogram films, radiologist-interpreted BI-RADS descriptors, and proteomic profiles of blood sera. We implemented under 100-fold cross-validation various classification algorithms, including Bayesian probit regression, iterated Bayesian model averaging, linear discriminant analysis, artificial neural networks, as well as a novel method of decision fusion. The top-performing classifier, decision fusion achieved AUC = 0.85 0.01 on ... |
|
| Enhancement of Anti-Telomerase Immunity Against Prostate Cancer |
NOV 2006 |
18 pages |
| Authors:
Johannes Vieweg; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The overall objective of this proposal is to enhance the efficacy of cancer vaccines by selectively eliminating or reducing CD4+ regulatory T cells (Treg) expressing the high affinity CD25 IL-2-specific receptor (IL-2R) in patients with metastatic prostate cancer. Preclinical and clinical data from our laboratory (see Reference 1 and Appendix A) and others (2, 3) have shown that CD4+/CD25+ Treg play an important role in the suppression of T cell ... |
|
| Biological Basis for Chemoprevention of Ovarian Cancer |
OCT 2006 |
60 pages |
| Authors:
Andrew Berchuck; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| To achieve a better understanding of the etiology of ovarian cancer we have initiated a case-control study that considers genetic susceptibility epidemiologic risk factors and acquired genetic alterations. Subjects are interviewed in their homes and about 950 cases and 950 controls have been accrued thus far. Blood and cancer samples have been collected and molecular analyses of polymorphisms in single genes including most recently the androgen receptor have been performed. ... |
|
| CBP and Extracellular Matrix-Induced Apoptosis in p53(-) HMECs: A Model of Early Mammary Carcinogenesis |
SEP 2006 |
129 pages |
| Authors:
Victoria Seewaldt; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Interactions between normal mammary epithelial cells (HMECs) and extracellular matrix (ECM) are important for mammary gland homeostasis and loss of ECM-sensitivity is an early event in mammary carcinogenesis. The purpose of this grant is to investigate how the CREBP-binding protein (CBP) might target the elimination of damaged HMECs. We have observed that 1) suppression of CBP results in apoptosis-resistance through impaired laminin expression and 2) CBP promotes induction of interferon-regulated ... |
|
| Increasing Sustained Participation in Free Mass Prostate Cancer Screening Clinics |
MAY 2006 |
115 pages |
| Authors:
Marva M. Price; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The overall objective of this study was to determine factors associated with sustaining regular participation in free prostate cancer screening clinics, particularly among African American men. Intervention strategies were designed and used at the community level by nurses in free screening clinics to improve screening sustainability. Strategies used in this study show that African American participation can be increased significantly. Men will respond to tailored messages. African American men who ... |
|
| Partnering Research Involving Mentoring and Education (PRIME) in Prostate Cancer |
FEB 2006 |
34 pages |
| Authors:
Marva M. Price; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Partnering Research Involving Mentoring and Education in Prostate Cancer (PRIME) is a partnership between two nursing schools, Duke University School of Nursing and North Carolina Central University (NCCU), an historically black college or university (HBCU). Our goal is to build a collaborative relationship between Duke University and NCCU that brings together students and faculty mentors to facilitate opportunities for underrepresented minority students to learn about prostate cancer. To accomplish this ... |
|
| Epigenetic Characterization of Ovarian Cancer |
DEC 2005 |
8 pages |
| Authors:
Susan K. Murphy; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The purpose of this research project is to identify genes that are hypermethylated in epithelial ovarian cancers on a genome-wide scale and determine if this is histology-specific. The approach is to use normal ovarian surface epithelium (NOSE) and malignant cells obtained directly from surgically removed specimens in order to most closely approximate the methylation status in vivo. Cultured cells are mock treated, or treated with 5-AzaC, a potent DNA methyltransferase ... |
|
| Enhancement of Anti-Telomerase Immunity Against Prostate Cancer |
NOV 2005 |
19 pages |
| Authors:
Johannes W. Vieweg; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The overall objective of this proposal is to enhance the efficacy of cancer vaccines by selectively eliminating or reducing CD4+ regulatory T cells (Treg) expressing the high affinity CD25 IL-2-specific receptor (IL-2R) in patients with metastatic prostate cancer. Preclinical and clinical data from our laboratory and others have shown that CD4+/CD25+ Treg play an important role in the suppression of T cell responses and that elimination of Treg is capable ... |
|
| Biological Basis for Chemoprevention of Ovarian Cancer |
OCT 2005 |
46 pages |
| Authors:
Andrew Berchuck; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The rationale for ovarian cancer prevention is highlighted by the observations that pregnancy and birth control pill use are strongly protective. To achieve a better understanding of the etiology of ovarian cancer, which can then be translated into effective prevention strategies, we have initiated a case-control study that considers genetic susceptibility, epidemiologic risk factors and acquired genetic alterations. Subjects are interviewed in their homes and about 800 cases and 850 ... |
|
| Regulation of Apoptosis by AFG3L2, a Potential Oncogene |
01 AUG 2005 |
7 pages |
| Authors:
Zachary Schafer; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Apoptosis, or programmed cell death, is frequently triggered through the release of cytochrome c from mitochondria. Cytosolic cytochrome c then binds to a cytosolic protein known as Apaf-1, which binds to and activates the cell death protease, caspase 9. Many cancers are resistant to apoptosis induced by chemotherapies. During the course of this work we demonstrated that breast cancer cells, while resistant to release of mitochondrial cytochrome c are actually ... |
|
| Reaper-Induced Apoptosis |
AUG 2005 |
6 pages |
| Authors:
Jennifer Perry; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Reaper is a central regulator of apoptosis in the fly, Drosophila melanogaster. At the start of this proposal our laboratory identified what was believed to be a pro-apoptotic human homolog of Reaper. This was of extreme interest as no true Reaper homolog had been identified in any organism. Accordingly, we proposed in the original statement of work to investigate the ability of the isolated gene to a) induce apoptosis upon ... |
|
| Reaper-Induced Cytochrome C Release |
AUG 2005 |
6 pages |
| Authors:
Eugene Gan; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Apoptosis is a program of cellular suicide that removes individual cells from the midst of a living tissue without destroying overall tissue architecture. In response to chemotherapeutic agents, cells die by apoptosis. Moreover, inhibition of apoptosis is a hallmark of cancers. In this proposal, we proposed to understand the molecular basis for apoptosis induced by the proapoptotic protein, Reaper. Having purified and characterized a protein, Scythe, acting downstream of Reaper ... |
|
| The Role of GADD34 (Growth Arrest and DNA Damage-Inducible Protein) in Regulating Apoptosis, Proliferation, and Protein Synthesis in Human Breast Cancer Cells |
JUL 2005 |
|
| Authors:
Douglas C. Welser; DUKE UNIV MEDICAL CENTER DURHAM NC
|
 | The proto-oncogene c-myc has been widely implicated in human cancer'. One of the major cellular targets of c-myc is the stress-induced gene GADD34. GADD34 is a potent apoptotic-inducer, but c-myc expression potently inhibits GADD34 expression, indicating that GADD34 may be an important target of c-myc-mediated oncogenesis2. (3ADD34 is a scaffolding protein that interacts with several proteins including Protein Phosphatase 1 (PP1) and a PP1 inhibitor, Inhibitor-1 (I-1) sub 3. GADD34 ... |
|
| Design and Clinical Efficacy of a Computer-Aided Detection Tool for Masses in Mammograms |
JUN 2005 |
108 pages |
| Authors:
Swatee Singh; Joseph Lo; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Our hypothesis is that a highly sensitive and highly specific CAD scheme, incorporating unique preprocessing techniques and advanced Decision Theory methods, can detect masses and improve the performance of mammographers. To test this hypothesis, we propose to construct a CAD system from two key components: 1) a highly sensitive mass detector, and 2) statistical models designed to reduce false-positives. We feel that it is essential to develop a tool that ... |
|
| Increasing Sustained Participation in Free Mass Prostate Cancer Screening Clinics |
MAY 2005 |
37 pages |
| Authors:
Marva Price; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The overall objective of this study is to determine factors associated with sustaining regular participation in free prostate cancer screening clinics among African American men. The expected outcome will be to define a set of intervention strategies that can be conducted at the community level by nurses in free screening clinics or programs. This study will provide understanding of the factors that influence African American men's choice to sustain participation ... |
|
| Novel Gbeta Mimic Kelch Proteins Gpb1 and Gpb2 Connect G-Protein Signaling to Ras Via Yeast Neurofibromin Homologs Ira 1 and Ira 2: A Model for Human NF1 |
MAR 2005 |
43 pages |
| Authors:
Joseph Heitman; Toshiaki Harashima; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The Neurofibromatosis type 1 (NF1) gene encodes a large tumor suppressor protein, neurofibromin, which is a Ras GTPase-activating protein (RasGAP) activity. Although the NF1 gene was identified over a decade ago, the biological roles of neurofibromin in cellular processes remain unclear. Therefore it is crucial for therapy and developing new drugs for NF1 patients to elucidate how the RasGAP activity of neurofibromin is controlled. To achieve this goal, it is ... |
|
| Structural and Functional Analysis of Androgen Receptor-DNA Interactions |
FEB 2005 |
9 pages |
| Authors:
Daniel T. Gewirth; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Our objective was to use X-ray crystallography to determine the basis for specific interactions between the Androgen receptor and its DNA targets, in order to understand how the receptor can recognize two different bipartite DNA response elements with diametrically opposing arrangements. Our research has identified a variant of the AR DNA binding domain that yields large, single lattice crystals when bound to a direct repeat response element. The 3-dimensional crystal ... |
|
| Regulation of P53 Activity by Reversible-Acetylation in Prostate Tumor Suppression |
JAN 2005 |
13 pages |
| Authors:
Yoshiharu Kawaguchi; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The importance of p53 on prostate cancer is underlined by clinical observations that p53 alteration can be seen in most metastatic prostate cancers. The finding that re-introduction of wild-type p53 can cause growth arrest of prostate cancer cells further support the role of p53 in prostate tumor suppression. Therefore, to study on prostate tumor development and a therapeutic strategy targeting p53, it is necessary to understand how p53 is activated. ... |
|
| Biological Basis for Chemoprevention of Ovarian Cancer |
OCT 2004 |
29 pages |
| Authors:
Andrew Berchuck; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The rationale for ovarian cancer prevention is highlighted by the observations that pregnancy and birth control pill use are strongly protective. To achieve a better understanding of the etiology of ovarian cancer, which can then be translated into effective prevention strategies, we have initiated a case-control study that considers genetic susceptibility, epidemiologic risk factors and acquired genetic alterations. Subjects are interviewed in their homes and about 750 cases and 750 ... |
|
| Relationships of Stress Exposures to Health in Gulf War Veterans |
OCT 2004 |
30 pages |
| Authors:
John A. Fairbank; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Despite nearly a decade of research, lack of consensus remains about the precise nature, etiology, and significance of Gulf War veterans' health concerns. No widely accepted case definition for Gulf War illness exists and controversy persists about whether Gulf War veterans symptoms "should be considered primarily a part of a general phenomenon that occurs in every war or a consequence of events and exposures unique to the Gulf War" (Steele, ... |
|
| CBP and Extracellular Matrix-Induced Apoptosis in p53 (-) HEMECs: A model of Early Mammary Carcinogenesis |
SEP 2004 |
168 pages |
| Authors:
Victoria L. Seewaldt; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Interactions between normal mammary epithelial cells (HMECs) and extracellular matrix (ECM) are important for mammary gland homeostasis and loss of ECM-sensitivity is an early event in mammary carcinogenesis. The purpose of this grant is to investigate how the CREBP-binding protein (CBP) might target the elimination of damaged HMECs. We have observed that 1) suppression of CBP results in apoptosis-resistance through impaired laminin expression and 2) CBP promotes induction of interferon-regulated ... |
|
| Analysis of the Link Between Acquired Expression of a Master Switch Gene of Osteoblast Differentiation by Breast Cancer and Bone Metastasis |
AUG 2004 |
10 pages |
| Authors:
Xiao-Fan Wang; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Bone metastasis of breast cancer is a major cause of death among breast cancer patients. However, we still know relatively little about why many breast cancers metastasize to the bone. To develop better treatments of bone - metastasis of breast cancer, we need to understand how breast cancer cells acquire the abilities to move to the bone, survive in the new environment, and flourish as metastatic tumors. We postulate that ... |
|
| Regulation of Cdc42/Rac Signaling in the Establishment of Cell Polarity and Control of Cell Motility |
AUG 2004 |
66 pages |
| Authors:
Javier E. Irazoqui; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Cdc42p, together with other polarity proteins, becomes polarize to a cap at the presumptive bud site and the tip of the emerging bud. The initial observation that Cdc42p is able to polarize, and remain polarized, in the complete absence of F-actin (Ayscough et al., 1997), has been confirmed repeatedly by many laboratories (including ours). These studies use Lat-A as a quick, effective method to completely depolymerize actin, and led to ... |
|
| The Role of GADD34 (Growth Arrest and DNA Damage-Inducible Protein) in Regulating Apoptosis, Proliferation, and Protein Synthesis in Human Breast Cancer Cells |
JUL 2004 |
11 pages |
| Authors:
Douglas C. Weiser; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| GADD34 is a stress-induced proteins implicated in the control of protein synthesis and apoptosis. It is a major target of the oncogene c-myc. Myc is widely implicated in breast cancer and potently inhibits GADD34 expression. The goal of this proposal is to better understand the mechanism of GADD34 induced apoptosis and the implications of this to human breast cancer. Toward this goal we have analyzed the regulation of eIF2 alpha ... |
|
| Functional Analysis of p53 Acetylation in Prostate Tumor Suppression |
JUL 2004 |
59 pages |
| Authors:
Tso-Pang Yao; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The tumor suppressor p53 becomes acetylated upon its activation. We show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all known acetylated lysines in vivo. Fibroblasts over-expressing a dominant negative HDAC1 mutant display enhanced DNA damage-induced p53 acetylation, increased levels of p53, and a more pronounced induction of p21 and MDM2. These results ... |
|
| Functional Characterization of TPF (Tumor Promoting Factor), A Novel Angiogenic Factor in Breast Cancer Pathogenesis |
JUN 2004 |
25 pages |
| Authors:
Rong Shao; Xiao-Fan Wang; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The later stages of human cancer development are poorly understood complex processes associated with the expression of genes by cancers that promote specific tumorigenic activities, such as angiogenesis and metastasis. In the present study, we identified periostin whose acquired expression by human cancers leads to a significant enhancement in tumor angiogenesis and metastasis. Undetectable in normal human breast tissues, periostin was found to be overexpressed by human primary breast cancers ... |
|
| Definition of the Molecular Mechanisms Which Distinguish Between Selective Estrogen Receptor Modulators (SERMs) and Full Antiestrogens |
MAY 2004 |
15 pages |
| Authors:
Huey-Jing Huang; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The antiestrogen tamoxifen is the most commonly used endocrine treatment for all stages of breast cancer. Tamoxifen is a SERM (Selective Estrogen Receptor Modulator) which can act as an estrogen or an antiestrogen depending on the tissues in which it operates. Initially, tamoxifen may have profound effects on the survival and proliferation of breast cancer cells, but progressively, resistance emerges through mechanisms that are only partially understood. Some pure antiestrogens ... |
|
| Structural and Functional Analysis of Androgen Receptor-DNA Interactions |
FEB 2004 |
8 pages |
| Authors:
Daniel T. Gewirth; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Our objective is to use X-ray crystallography to determine the basis for specific interactions between the Androgen receptor and its DNA targets, in order to understand how the receptor can recognize two different bipartite DNA response elements with diametrically opposing arrangements. Our research has now identified a variant of the AR DNA binding domain that yields large, single lattice crystals when bound to a direct repeat response element. The 3- ... |
|
| Relationships of Stress Exposures to Health in Gulf War Veterans |
OCT 2003 |
38 pages |
| Authors:
John A. Fairbank; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Research on Gulf War (6W) illnesses leaves many questions unanswered about diagnostic syndromes of 6W illnesses, dimensions of stressor exposures encountered by 6W veterans, relations among stressor exposures and GW syndromes or symptoms, and factors that may mediate these relationships. The proposed study has five key aims intended to address these gaps and enhance understanding of illnesses reported by 6W veterans: (1) to identify and examine dimensions of illnesses and ... |
|
| Gene Regulation by Retinoid Receptors in Human Mammary Epithelial Cells |
OCT 2003 |
116 pages |
| Authors:
Victoria L. Seewaldt; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Based on Preliminary Data, we hypothesized that loss of retinoic acid receptor function might promote dysregulated growth and loss of epithelial polarity. We now report that retinoids and the retinoic acid receptor-beta are important regulators of proliferation and polarity normal mammary epithelial cells through modulation of 1) the CREB-binding protein, CBP and 2) laminin 5 expression. As proposed in Objective lA, and described in the BODY of this report, we ... |
|
| Biological Basis for Chemoprevention of Ovarian Cancer |
OCT 2003 |
34 pages |
| Authors:
Andrew Berchuck; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The rationale for ovarian cancer prevention is highlighted by the observations that pregnancy and birth control pill use are strongly protective. To achieve a better understanding of the etiology of ovarian cancer, which can then be translated into effective prevention strategies, we have initiated a case-control study that considers genetic susceptibility, epidemiologic risk factors and acquired genetic alterations. Subjects are interviewed in their homes and about 650 cases and 650 ... |
|
| CBP and Extracellular Matrix-Induced Apoptosis in p53(-) HMECs: A Model of Early Mammary Carcinogenesis |
SEP 2003 |
75 pages |
| Authors:
Victoria L. Seaweldt; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Interactions between normal mammary epithelial cells (HMECs) and extracellular matrix (ECM) are important for mammary gland homeostasis and loss of ECM-sensitivity is an early event in mammary carcinogenesis. The purpose of this grant is to investigate how the CREBP-binding protein (CBP) might target the elimination of damaged HMECs. We have observed that 1) suppression of CBP results in apoptosis-resistance through impaired laminin expression and 2) CBP promotes induction of interferon-regulated ... |
|
| Identification of Proteins Essential for Telomere Elongation |
AUG 2003 |
39 pages |
| Authors:
Soma Banik; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| A critical challenge in creating novel therapeutic agents in the treatment of breast cancer is the identification of cellular processes and molecular targets that differentiate normal and neoplastic tissue. One of the most consistent changes to occur n breast cancer is cellular immortalization through the upregulation of hTERT, which encodes the catalytic subunit of the telomerase ribonucleoprotein holoenzyme. Recently, we have identified the RNA binding domain of hTERT, and found ... |
|
| Regulation of Cdc42/Rac Signaling in the Establishment of Cell Polarity and Control of Cell Motility |
AUG 2003 |
55 pages |
| Authors:
Javier E. Irazoqui; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Cdc42p and other proteins polarize to a cap at the presumptive bud site and the tip of the bud. The observation that Cdc42p polarizes in the complete absence of F-actin has been confirmed repeatedly. These studies used LatA as a method to completely depolymerize actin, and suggested that Cdc42p polarization is actin-independent. Polarized secretion and endocytic uptake require F-actin cables and patches, respectively. When LatA is applied to yeast cells ... |
|
| The Role of GADD34 (Growth Arrest and DNA Damage-Inducible Protein) in Regulating Apoptosis, Proliferation, and Protein Synthesis in Human Breast Cancer Cells |
JUL 2003 |
18 pages |
| Authors:
Douglas C. Weiser; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| GADD34 is a stress-induced proteins implicated in the control of protein synthesis and apoptosis. It is a major target of the oncogene c-myc. Myc is widely implicated in breast cancer and potently inhibits GADD34 expression. The goal of this proposal is to better understand the mechanism of GADD34 induced apoptosis and the implications of this to human breast cancer. Toward this goal we have analyzed the regulation of eIF2 alpha ... |
|
| Functional Analysis of p53 Acetylation in Prostate Tumor Suppression |
JUL 2003 |
41 pages |
| Authors:
Tso-Pang Yao; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The tumor suppressor p53 is stabilized and activated in response to cellular stress through post translational modifications including acetylation. p300/CBP-mediated acetylation of p53 is negatively regulated by MDM2. We show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all known acetylated lysines in vivo. Ectopic expression of a dominant negative HDAC1 mutant restores ... |
|
| Toxic Interactions of Prophylactic Drugs and Pesticides |
JUL 2003 |
230 pages |
| Authors:
Mohamed B. Abou-Donia; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The goal of this project is to evaluate the mechanisms of interactive effects of exposure to the insect repellant, DEET, the insecticide, permethrin, and anti-nerve agent, pyridostigmine bromide (PB) and the biological and pathological consequences of such interactions. The hypothesis to be tested is that combined exposure to a mixture of chemicals would have enhanced, and in some cases detrimental toxicological effects than exposure with single chemical as result of ... |
|
| Apoptotic Regulation |
JUL 2003 |
9 pages |
| Authors:
David A. Richardson; Sally A. Kornbluth; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Reaper is a potent inducer of apoptotic cell death in the fruit fly Drosoophila melanogaster. Our lab unexpectedly discovered that Reaper also induces apoptosis in cultured human cells and cell free extracts prepared using eggs from the frog Xenopus laevis. In the Xenopus model system Reaper must bind another protein, Scythe, to induce apoptosis. Scythe forms a stable complex with the chaperone protein Hsp70 and inhibits its activity. Upon Reaper-Scythe ... |
|
| Functional Characterization of TPF (Tumor Promoting Factor), a Novel Angiogenic Factor in Breast Cancer Pathogenesis |
JUN 2003 |
11 pages |
| Authors:
Rong Shao; Xiao-Fan Wang; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The primary goal of this project is to test the hypothesis that a newly identified protein, periostin, functions as an angiogenic factor to promote tumor progression and metastasis. As our previous results support this assumption, we in this final report have conducted additional experiments to generate substantial evidence for strengthening our conclusion. We wish to firmly establish an important functional role for periostin in the pathological process of breast carcinogenesis ... |
|
| The Role of the Polypyrimidine Tract Binding Protein on CD44 Splicing in Breast Cancer |
JUN 2003 |
144 pages |
| Authors:
Andrew Baraniak; Mariano A. Garcia-Blanco; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The cytogenetic and nuclear changes during breast tumor progression have been well documented, but the causes of these alterations are poorly understood. Changes in estrogen receptor status, gain in metastatic potential, accumulation of PNCs, and differential splicing of genes are changes seen in breast cancer cells during tumor progression. A strong connection between the splicing machinery and these subtle, significant, changes in gene expression have yet to be documented. Likely ... |
|
| Definition of the Molecular Mechanisms Which Distinguish Between Selective Estrogen Receptor Modulators (SERMs) and Full Antiestrogens |
MAY 2003 |
12 pages |
| Authors:
Huey-Jing Huang; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Tamoxifen, a SERM (Selective Estrogen Receptor Modulator), is the most commonly used endocrine treatment for all stages of breast cancer. However, progression from tamoxifen sensitivity to tamoxifen resistance occurs in a substantial portion of the tumors. Full antiestrogens, such as ICI 182,780, are currently used as the second line therapy after failure of long-term tamoxifen therapy. To facilitate the design and characterization of more appropriate therapeutic agents for endocrine therapy ... |
|
| Functional Analysis of the Transcriptional Co-Activator CBP in Wnt- Signaling Dependent |
MAY 2003 |
15 pages |
| Authors:
Tso-Pang Yao; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Wnt signaling is mediated by a multi-components cascade that relays the signal from cell membrane to nuclear TCF-BETA- catenin transcriptional complex. Genetic study has implicated CREB-Binding Protein (CEP) as a negative regulator of Wnt signaling. We initially found that CBP can acetylate TCF4, the key transcriptional effector in the wnt signaling pathway. Furthermore, we also found that CBP and beta-catenin, another key element of the wnt signaling, forms a complex. ... |
|
| Functional Role of the Casein Kinase I (CKI) Family in the Transforming Growth Factor-Beta (TGF-Beta) Signaling Pathway |
APR 2003 |
49 pages |
| Authors:
David Waddell; Nicole T. Liberati; Xiao-Fan Wang; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The regulation of the Transforming Growth Factor-Beta (TGF-Beta signaling pathway and its role in cancer is an area of intense research. We are investigating the regulatory role of casein kinase I (CKI) in the TGF-Beta signaling cascade. We have found that all CKI isoforms (alpha, delta, epsilon, and gamma) can bind to Smads in vitro and that this interaction is mediated through the Mad Homology 2 (MH2) domain of the ... |
|
| A Unique Class of Topoisomerase Mutants That Are Hypersensitive to Multiple Antitumor Agents |
MAR 2003 |
33 pages |
| Authors:
Erin K. O'Reilly; Kenneth Kreuzer; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| The goal of this research is to understand the detailed mechanism of action of antitumor drugs that target type II topoisomerases. Previous analysis showed that a drug resistant bacteriophage T4 mutant harbored two amino acid substitutions (S79F, G269V) in topoisomerase subunit gp52. When both mutations are present, the G269V substitution suppresses a topoisomerase negative phenotype caused by the S79F substitution while the G269V substitution by itself was shown to confer ... |
|
| Structural and Functional Analysis of Androgen Receptor-DNA Interactions |
FEB 2003 |
17 pages |
| Authors:
Daniel T. Gewirth; DUKE UNIV MEDICAL CENTER DURHAM NC
|
| Our objective is to use X-ray crystallography to determine the basis for specific interactions between the Androgen receptor and its DNA targets, in order to understand how the receptor can recognize two different bipartite DNA response elements with diametrically opposing arrangements. Our research has now identified a variant of the AR DNA binding domain that yields large, single lattice crystals when bound to a direct repeat response element. These crystals ... |
|
Reports by Corporate Author
