26 results on '"Bourboulia, Dimitra"'
Search Results
2. Asymmetric Hsp90 N Domain SUMOylation Recruits Aha1 and ATP-Competitive Inhibitors.
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Mollapour, Mehdi, Bourboulia, Dimitra, Beebe, Kristin, Woodford, Mark?R., Polier, Sigrun, Hoang, Anthony, Chelluri, Raju, Li, Yu, Guo, Ailan, Lee, Min-Jung, Fotooh-Abadi, Elham, Khan, Sahar, Prince, Thomas, Miyajima, Naoto, Yoshida, Soichiro, Tsutsumi, Shinji, Xu, Wanping, Panaretou, Barry, Stetler-Stevenson, William?G., and Bratslavsky, Gennady
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HEAT shock proteins , *POST-translational modification , *ADENOSINE triphosphatase , *CELLULAR signal transduction , *MOLECULAR chaperones , *HYDROLYSIS - Abstract
Summary: The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90’s function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs. [ABSTRACT FROM AUTHOR]
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- 2014
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3. Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells.
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Iwai, Aki, Bourboulia, Dimitra, Mollapour, Mehdi, Jensen-Taubman, Sandra, Sunmin Lee, Donnelly, Alison C., Yoshida, Soichiro, Miyajima, Naoto, Tsutsumi, Shinji, Smith, Armine K., Sun, David, Xiaolin Wu, Blagg, Brian S., Trepel, Jane B., Stetler-Stevenson, William G., and Neckers, Len
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- 2012
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4. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion
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Bourboulia, Dimitra and Stetler-Stevenson, William G.
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METALLOPROTEINASES , *ENZYME inhibitors , *CELL adhesion , *METASTASIS , *CANCER cells , *EXTRACELLULAR matrix , *CELL adhesion molecules - Abstract
Abstract: Cells adhere to one another and/or to matrices that surround them. Regulation of cell–cell (intercellular) and cell–matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of human cancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell property engaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPs degrade the ECM and, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue inhibitors of metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression. [ABSTRACT FROM AUTHOR]
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- 2010
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5. Kaposi's Sarcoma-Associated Herpesvirus Cytotoxic T Lymphocytes Recognize and Target Darwinian Positively Selected Autologous K1 Epitopes.
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Stebbing, Justin, Bourboulia, Dimitra, Johnson, Margaret, Henderson, Stephen, Williams, Ian, Wilder, Natalie, Tyrer, Mervyn, Youle, Mike, Imami, Nesrina, Kobu, Toru, Kuon, Wolfgang, Sieper, Joachim, Gotch, Frances, and Boshoff, Chris
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KAPOSI'S sarcoma , *HERPESVIRUS diseases , *HIV infections - Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution. [ABSTRACT FROM AUTHOR]
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- 2003
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6. Prospective Study of the Effects of Antiretroviral Therapy on Kaposi Sarcoma-Associated Herpesvirus Infection in Patients With and Without Kaposi Sarcoma.
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Gill, Jasjit, Bourboulia, Dimitra, Wilkinson, John, Hayes, Peter, Cope, Alethea, Marcelin, Anne-Genevieve, Calvez, Vincent, Gotch, Frances, Boshoff, Christopher, and Gazzard, Brian
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HERPESVIRUS disease treatment , *KAPOSI'S sarcoma , *HIV-positive persons , *THERAPEUTICS - Abstract
Investigates the effect of highly active antiretroviral therapy on circulating Kaposi sarcoma (KS)-associated herpesvirus (KSHV) load in HIV-infected individuals with and without KS. Use of adult clinical trials group criteria; Determination of plasma HIV-1 load, CD4 cell count; Titers of antibody to KSHV.
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- 2002
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7. Seroprevalence of human herpesvirus 8 and its association with Kaposi sarcoma in Brazil.
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Zago, Adriana, Bourboulia, Dimitra, Zago, A, Bourboulia, D, Viana, M C, Collandre, H, Dietze, R, Boshoff, C, and Keller, R
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HERPESVIRUSES , *KAPOSI'S sarcoma , *SEXUAL orientation , *HEPATITIS B - Abstract
Background: Epidemiologic studies have indicated that human herpesvirus 8 is implicated in the development of Kaposi sarcoma in different geographic areas worldwide.Goal: To provide information on the prevalence of human herpesvirus 8 in Brazil and its association with Kaposi sarcoma.Study Design: An immunofluorescence assay was performed to test 1,044 serum samples from 747 blood donors, 73 patients presenting to casualty departments, and 224 patients attending sexually transmitted disease/AIDS clinics. The sexually transmitted disease group was composed of 88 patients with HIV (40 Kaposi sarcoma positive, 48 Kaposi sarcoma negative) and 136 patients without HIV.Results: Antibodies to human herpesvirus 8-latent nuclear antigens were found in 34 blood donors (4.6%), and in seven casualty patients (9.6%). The highest frequency of human herpesvirus 8 antibodies was found in the sexually transmitted disease group: 32 HIV-positive patients with Kaposi sarcoma (80%) and seven patients without Kaposi sarcoma (14.6%).Conclusion: The presence of human herpesvirus 8 in patients with HIV was strongly associated with Kaposi sarcoma (odds ratio, 23.4; 95% CI, 7.7-71.4), male gender, homosexual or bisexual orientation, and hepatitis B virus infection, but not with the other sexually transmitted diseases that were investigated. [ABSTRACT FROM AUTHOR]- Published
- 2000
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8. TRAP1 Chaperones the Metabolic Switch in Cancer.
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Wengert, Laura A., Backe, Sarah J., Bourboulia, Dimitra, Mollapour, Mehdi, and Woodford, Mark R.
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HEAT shock proteins , *MOLECULAR chaperones , *POST-translational modification , *PERMEABILITY , *GLYCOLYSIS , *CELL death - Abstract
Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or 'clients'. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Serologic Evidence for Mother-to-Child Transmission of Kaposi Sarcoma–Associated Herpesvirus Infection.
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Bourboulia, Dimitra, Whitby, Denise, Boshoff, Chris, Newton, Robert, Beral, Valerie, Carrara, Henri, Lane, Anthony, and Sitas, Freddy
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- 1998
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10. Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer.
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Backe, Sarah J., Sager, Rebecca A., Meluni, Katherine A., Woodford, Mark R., Bourboulia, Dimitra, and Mollapour, Mehdi
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MOLECULAR chaperones , *HEAT shock proteins , *TUBEROUS sclerosis , *CELL physiology , *RENAL cell carcinoma - Abstract
Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases. [ABSTRACT FROM AUTHOR]
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- 2022
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11. LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds pRB and represses E2F-driven transcription.
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Sharp, Tyson V., Munoz, Fernando, Bourboulia, Dimitra, Presneau, Nadege, Darai, Eva, Hsei-Wei Wang, Cannon, Mark, Butchers, David N., Nicholson, Andrew G., Klein, George, Imreh, Stephan, and Boshoff, Chris
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PROTEINS , *CHROMOSOMES , *RETINOBLASTOMA , *RETINA cancer , *TUMOR growth , *LUNG cancer - Abstract
LIM domains-containing protein 1 (LIMD1) is encoded at chromosome 3p21.3, a region commonly deleted in many solid malignancies. However, the function of LIMD1 is unknown. Here we show that LIMD1 specifically interacts with retinoblastoma protein (pRB), inhibits E2F-mediated transcription, and suppresses the expression of the majority of genes with E2F1-responsive elements. LIMD1 blocks tumor growth in vitro and in vivo and is down-regulated in the majority of human lung cancer samples tested. Our data indicate that LIMD1 is a tumor-suppressor gene, the protein product of which functionally interacts with pRB and the loss of which promotes lung carcinogenesis. [ABSTRACT FROM AUTHOR]
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- 2004
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12. The 2021 FASEB Virtual Catalyst Conference on Extracellular and Organismal Proteostasis in Health and Disease, February 3-4, 2021.
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Lior, Chen, Hodge, Francesca, De-Souza, Evandro A., Bourboulia, Dimitra, Calderwood, Stuart K., David, Della, Drummond, D. Allan, Edkins, Adrienne, Morimoto, Richard I., Prahlad, Veena, Rechavi, Oded, Sistonen, Lea, Wilson, Mark, Wiseman, R. Luke, Zanetti, Maurizio, Taylor, Rebecca, Scherz-Shouval, Ruth, and van Oosten-Hawle, Patricija
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- 2021
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13. The Role of Heat Shock Protein-90 in the Pathogenesis of Birt-Hogg-Dubé and Tuberous Sclerosis Complex Syndromes.
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Woodford, Mark R, Backe, Sarah J, Sager, Rebecca A, Bourboulia, Dimitra, Bratslavsky, Gennady, and Mollapour, Mehdi
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TUBEROUS sclerosis , *KIDNEY tumors , *RENAL cell carcinoma , *MOLECULAR chaperones , *SYNDROMES , *ANGIOMYOLIPOMA - Abstract
Birt-Hogg-Dubé (BHD) and tuberous sclerosis (TS) syndromes share many clinical features. These two diseases display distinct histologic subtypes of renal tumors: chromophobe renal cell carcinoma and renal angiomyolipoma, respectively. Early work suggested a role for mTOR dysregulation in the pathogenesis of these two diseases, however their detailed molecular link remains elusive. Interestingly, a growing number of case reports describe renal angiomyolipoma in BHD patients, suggesting a common molecular origin. The BHD-associated proteins FNIP1/2 and the TS protein Tsc1 were recently identified as regulators of the molecular chaperone Hsp90. Dysregulation of Hsp90 activity has previously been reported to support tumorigenesis, providing a potential explanation for the overlapping phenotypic manifestations in these two hereditary syndromes. [ABSTRACT FROM AUTHOR]
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- 2021
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14. MMPs, tyrosine kinase signaling and extracellular matrix proteolysis in kidney cancer.
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Hashmi, Fiza, Mollapour, Mehdi, Bratslavsky, Gennady, and Bourboulia, Dimitra
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PROTEIN-tyrosine kinases , *RENAL cancer , *EXTRACELLULAR matrix , *MATRIX metalloproteinases , *PROTEOLYSIS , *PROTEOLYTIC enzymes , *RENAL cell carcinoma , *METABOLISM , *CELLULAR signal transduction , *KIDNEY tumors , *EXTRACELLULAR space - Abstract
Patients diagnosed with metastatic renal cell carcinoma (RCC) have ∼12% chance for 5-year survival. The integrity of the extracellular matrix (ECM) that surrounds tumor cells influences their behavior and, when disturbed, it could facilitate local invasion and spread of tumor cells to distant sites. The interplay between von Hippel-Lindau/hypoxia inducible factor signaling axis and activated kinase networks results in aberrant ECM and tumor progression. Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in ECM remodeling, tumor angiogenesis, and immune cell infiltration. Understanding the cross-talk between kinase signaling and ECM proteolysis in RCC could provide insights into developing drugs that interfere specifically with the process of invasion. In this review, we discuss changes in the MMPs/ECM axis in RCC, prominent kinase signaling pathways implicated in MMPs induction, and comment on emerging extracellular regulatory networks that modulate MMPs activity. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Viral Coinfections among African Children Infected with Human Immunodeficiency Virus Type 1.
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Chakroborty, Rana, Rees, Gareth, Bourboulia, Dimitra, Cross, Alexandra M., Dixon, Jedediah R., D'Agostino, Angelo, Musoke, Rachel, Boshoff, Chris, Rowland-Jones, Sarah L., and Klenerman, Paul
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HIV-positive persons , *CYTOMEGALOVIRUS diseases , *HERPESVIRUS diseases , *HEPATITIS viruses - Abstract
City-dwelling children from Kenya who were infected with human immunodeficiency virus type 1 (HIV-1) were tested for coinfection with cytomegalovirus (CMV), human T cell lymphotropic viruses 1 and 2, Kaposi sarcoma-associated herpesvirus (KSHV), or hepatitis B, C, and G viruses. All children were found to be coinfected with CMV, whereas 5% had hepatitis G virus coinfection and 15% had KSHV coinfection. A protective role for hepatitis G virus cannot be excluded but likely affects only a minority of HIV-1-infected African children. [ABSTRACT FROM AUTHOR]
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- 2003
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16. Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90–Client Interactions.
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Paladino, Antonella, Woodford, Mark R., Backe, Sarah J., Sager, Rebecca A., Kancherla, Priyanka, Daneshvar, Michael A., Chen, Victor Z., Bourboulia, Dimitra, Ahanin, Elham F., Prodromou, Chrisostomos, Bergamaschi, Greta, Strada, Alessandro, Cretich, Marina, Gori, Alessandro, Veronesi, Marina, Bandiera, Tiziano, Vanna, Renzo, Bratslavsky, Gennady, Serapian, Stefano A., and Mollapour, Mehdi
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ONCOGENIC proteins , *PROTEIN folding , *GLUCOCORTICOID receptors , *FORECASTING , *NUCLEAR magnetic resonance , *MOLECULAR chaperones , *HEAT shock proteins - Abstract
Protein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein‐90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co‐chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c‐Abl, c‐Src, Cdk4, B‐Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90‐system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein–protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation. [ABSTRACT FROM AUTHOR]
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- 2020
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17. Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer.
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Ahanin, Elham F., Sager, Rebecca A., Backe, Sarah J., Dunn, Diana M., Dushukyan, Natela, Blanden, Adam R., Mate, Nilamber A., Suzuki, Tamie, Anderson, Tyler, Roy, Merin, Oberoi, Jasmeen, Prodromou, Chrisostomos, Nsouli, Imad, Daneshvar, Michael, Bratslavsky, Gennady, Woodford, Mark R., Bourboulia, Dimitra, Chisholm, John D., and Mollapour, Mehdi
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PHOSPHOPROTEIN phosphatases , *RENAL cancer , *PHOSPHATASE inhibitors , *DEATH receptors , *BCL genes , *CATALYTIC domains , *MOLECULAR chaperones , *SERINE/THREONINE kinases , *LIGANDS (Biochemistry) - Abstract
Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer. [Display omitted] • PP5 mediates dephosphorylation and inactivation of the death effector protein FADD • PP5 maintains the integrity of complex II and regulates the extrinsic apoptosis • Development of competitive inhibitors of serine/threonine protein phosphatase-5 • Pharmacologic inhibition of PP5 activates the extrinsic apoptosis in renal cancer Ahanin et al. show that protein phosphatase-5 (PP5) down-regulates the extrinsic apoptotic pathway by dephosphorylating the death effector protein FADD, therefore preserving complex II integrity in cancer. A competitive inhibitor of PP5 designed in this study causes disruption of complex II and activation of extrinsic apoptotic pathway in renal cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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18. Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients.
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Woodford, Mark R, Sager, Rebecca A, Marris, Elijah, Dunn, Diana M, Blanden, Adam R, Murphy, Ryan L, Rensing, Nicholas, Shapiro, Oleg, Panaretou, Barry, Prodromou, Chrisostomos, Loh, Stewart N, Gutmann, David H, Bourboulia, Dimitra, Bratslavsky, Gennady, Wong, Michael, and Mollapour, Mehdi
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TUMOR suppressor proteins , *TUBEROUS sclerosis , *MOLECULAR chaperones , *HEAT shock proteins , *UBIQUITINATION , *MTOR inhibitors , *PROTEIN binding , *PROTEIN folding - Abstract
The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex ( TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteasomal degradation. [ABSTRACT FROM AUTHOR]
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- 2017
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19. Structural and functional basis of protein phosphatase 5 substrate specificity.
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Oberoi, Jasmeen, Dunn, Diana M., Woodford, Mark R., Mariotti, Laura, Schulman, Jacqualyn, Bourboulia, Dimitra, Mollapour, Mehdi, and Vaughan, Cara K.
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MOLECULAR chaperones , *PHOSPHOPROTEIN phosphatases , *IMMUNOSPECIFICITY , *HEAT shock proteins , *CRYSTAL structure - Abstract
The serine/threonine phosphatase protein phosphatase 5 (PP5) regulates hormone- and stress-induced cellular signaling by association with the molecular chaperone heat shock protein 90 (Hsp90). PP5-mediated dephosphorylation of the cochaperone Cdc37 is essential for activation of Hsp90-dependent kinases. However, the details of this mechanism remain unknown. We determined the crystal structure of a Cdc37 phosphomimetic peptide bound to the catalytic domain of PP5. The structure reveals PP5 utilization of conserved elements of phosphoprotein phosphatase (PPP) structure to bind substrate and provides a template for many PPP-substrate interactions. Our data show that, despite a highly conserved structure, elements of substrate specificity are determined within the phosphatase catalytic domain itself. Structure-based mutations in vivo reveal that PP5-mediated dephosphorylation is required for kinase and steroid hormone receptor release from the chaperone complex. Finally, our data show that hyper- or hypoactivity of PP5 mutants increases Hsp90 binding to its inhibitor, suggesting a mechanism to enhance the efficacy of Hsp90 inhibitors by regulation of PP5 activity in tumors. [ABSTRACT FROM AUTHOR]
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- 2016
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20. Swe1Wee1-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function
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Mollapour, Mehdi, Tsutsumi, Shinji, Donnelly, Alison C., Beebe, Kristin, Tokita, Mari J., Lee, Min-Jung, Lee, Sunmin, Morra, Giulia, Bourboulia, Dimitra, Scroggins, Bradley T., Colombo, Giorgio, Blagg, Brian S., Panaretou, Barry, Stetler-Stevenson, William G., Trepel, Jane B., Piper, Peter W., Prodromou, Chrisostomos, Pearl, Laurence H., and Neckers, Len
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TYROSINE , *PHOSPHORYLATION , *HEAT shock proteins , *SACCHAROMYCES , *PROTEIN-tyrosine kinases , *CHEMICAL inhibitors , *MOLECULAR chaperones , *ADENOSINE triphosphatase , *POST-translational modification - Abstract
Summary: Saccharomyces WEE1 (Swe1), the only “true” tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1Wee1 phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90α) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors. [Copyright &y& Elsevier]
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- 2010
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21. Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production.
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Funes, Juan M., Quintero, Marisol, Henderson, Stephen, Martinez, Dolores, Qureshi, Uzma, Westwood, Claire, Clements, Mark O., Bourboulia, Dimitra, Pedley, R. Barbara, Moncada, Salvador, and Boshoff, Chris
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STEM cells , *GLYCOLYSIS , *ADENOSINE triphosphate , *ADENINE nucleotides , *PHOSPHORYLATION , *CHEMICAL reactions - Abstract
An increased dependency on glycolysis for ATP production is considered to be a hallmark of tumor cells. Whether this increase in glycolytic activity is due mainly to inherent metabolic alterations or to the hypoxic microenvironment remains controversial. Here we have transformed human adult mesenchymal stem cells (MSC) using genetic alterations as described for differentiated cells. Our data suggest that MSC require disruption of the same pathways as have been shown for differentiated cells to confer a fully transformed phenotype. Furthermore, we found that MSC are more glycolytic than primary human fibroblasts and, in contrast to differentiated cells, do not depend on increased aerobic glycolysis for ATP production during transformation. These data indicate that aerobic glycolysis (the Warburg effect) is not an intrinsic component of the transformation of adult stem cells, and that oncogenic adaptation to bioenergetic requirements, in some circumstances, may also rely on increases in oxidative phosphorylation. We did find, however, a reversible increase in the transcription of glycolytic enzymes in tumors generated by transformed MSC, indicating this is a secondary phenomenon resulting from adaptation of the tumor to its microenvironment. [ABSTRACT FROM AUTHOR]
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- 2007
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22. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma.
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Wang, Hsei-Wei, Trotter, Matthew W. B., Lagos, Dimitrios, Bourboulia, Dimitra, Henderson, Stephen, Mäkinen, Taija, Elliman, Stephen, Flanagan, Adrienne M., Alitalo, Kari, and Boshoff, Chris
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KAPOSI'S sarcoma , *SARCOMA , *TUMORS , *GENE expression , *GENETIC regulation , *CELLS , *MOLECULES - Abstract
The biology of Kaposi sarcoma is poorly understood because the dominant cell type in Kaposi sarcoma lesions is not known. We show by gene expression microarrays that neoplastic cells of Kaposi sarcoma are closely related to lymphatic endothelial cells (LECs) and that Kaposi sarcoma herpesvirus (KSHV) infects both LECs and blood vascular endothelial cells (BECs) in vitro. The gene expression microarray profiles of infected LECs and BECs show that KSHV induces transcriptional reprogramming of both cell types. The lymphangiogenic molecules VEGF-D and angiopoietin-2 were elevated in the plasma of individuals with acquired immune deficiency syndrome and Kaposi sarcoma. These data show that the gene expression profile of Kaposi sarcoma resembles that of LECs, that KSHV induces a transcriptional drift in both LECs and BECs and that lymphangiogenic molecules are involved in the pathogenesis of Kaposi sarcoma. [ABSTRACT FROM AUTHOR]
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- 2004
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23. Risk factors for high anti-HHV-8 antibody titers (≥1:51,200) in black, HIV-1 negative South African cancer patients: a case control study.
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Wojcicki, Janet M., Newton, Rob, Urban, Margaret I., Stein, Lara, Hale, Martin, Patel, Moosa, Ruff, Paul, Sur, Ranjan, Bourboulia, Dimitra, and Sitas, Freddy
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HERPESVIRUSES , *KAPOSI'S sarcoma , *HIV , *VIRAL antibodies - Abstract
Background: Infection with human herpesvirus 8 (HHV-8) is the necessary causal agent in the development of Kaposi's sarcoma (KS). Infection with HIV-1, male gender and older age all increase risk for KS. However, the geographic distribution of HHV-8 and KS both prior to the HIV/AIDS epidemic and with HIV/AIDS suggest the presence of an additional co-factor in the development of KS. Methods: Between January 1994 and October 1997, we interviewed 2576 black in-patients with cancer in Johannesburg and Soweto, South Africa. Blood was tested for antibodies against HIV-1 and HHV-8 and the study was restricted to 2191 HIV-1 negative patients. Antibodies against the latent nuclear antigen of HHV-8 encoded by orf73 were detected with an indirect immunofluorescence assay. We examined the relationship between high anti-HHV-8 antibody titers (≥1:51,200) and sociodemographic and behavioral factors using unconditional logistic regression models. Variables that were significant at p = 0.10 were included in multivariate analysis. Results: Of the 2191 HIV-1 negative patients who did not have Kaposi's sarcoma, 854 (39.0%) were positive for antibodies against HHV-8 according to the immunofluorescent assay. Among those seropositive for HHV-8, 530 (62.1%) had low titers (1:200), 227 (26.6%) had medium titers (1:51,200) and 97 (11.4%) had highest titers (1:204,800). Among the 2191 HIV-1 negative patients, the prevalence of high anti-HHV-8 antibody titers (≥1:51,200) was independently associated with increasing age (ptrend = 0.04), having a marital status of separated or divorced (p = 0.003), using wood, coal or charcoal as fuel for cooking 20 years ago instead of electricity (p = 0.02) and consuming traditional maize beer more than one time a week (p = 0.02; p-trend for increasing consumption = 0.05) although this may be due to chance given the large number of predictors considered in this analysis. Conclusions: Among HIV-negative subjects, patients with high anti-HHV-8 antibody titers are characterized by older age. Other associations that may be factors in the development of high anti-HHV-8 titers include exposure to poverty or a low socioeconomic status environment and consumption of traditional maize beer. The relationship between these variables and high anti-HHV-8 titers requires further, prospective study. [ABSTRACT FROM AUTHOR]
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- 2003
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24. Comprehensive genomic profiling of metastatic collecting duct carcinoma, renal medullary carcinoma, and clear cell renal cell carcinoma.
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Bratslavsky, Gennady, Gleicher, Stephanie, Jacob, Joseph M., Sanford, Thomas H., Shapiro, Oleg, Bourboulia, Dimitra, Gay, Laurie M, Andrea Elvin, Julie, Vergilio, Jo-Anne, Suh, James, Ramkissoon, Shakti, Severson, Eric Allan, Killian, Jonathan Keith, Schrock, Alexa Betzig, Chung, Jon H., Miller, Vincent A., Mollapour, Mehdi, and Ross, Jeffrey S.
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RENAL cell carcinoma , *MEDULLARY thyroid carcinoma , *PROTEIN-tyrosine kinases , *CARCINOMA , *EPIDERMAL growth factor receptors , *METASTASIS , *CANCER cells , *GENETIC mutation , *GENE expression profiling , *KIDNEY tumors , *GENOMICS - Abstract
Introduction and Objective: Unlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy.Material and Methods: DNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations.Results: mCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb.Conclusion: Genomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies. [ABSTRACT FROM AUTHOR]- Published
- 2021
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25. Serologic Evidence of Human Herpesvirus 8 Transmission by Homosexual but Not Heterosexual Sex.
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Smith, Nicola A., Sabin, Caroline A., Gopal, Robin, Bourboulia, Dimitra, Labbet, Wendy, Boshoff, Chris, Barlow, David, Band, Barbara, Peters, Barry S., de Ruiter, Annemiek, Brown, David W.G., Weiss, Robin A., Best, Jennifer M., and Whitby, Denise
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HERPESVIRUSES , *SEXUALLY transmitted diseases , *SERODIAGNOSIS , *HETEROSEXUALS - Abstract
Presents a seroepidemiologic study that determines whether human herpesvirus 8 (HHV-8) is transmitted sexually between heterosexuals. Relationships between possible risk factors and HHV-8 infection; Independent risk factors for HHV-8; Overall seroprevalence of HHV-8.
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- 1999
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26. Antibodies against Human Herpesvirus 8 in Black South African Patients with Cancer.
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Sitas, Freddy, Carrara, Henri, Beral, Valerie, Newton, Rob, Reeves, Gillian, Bull, Diana, Jentsch, Ute, Pacella-Norman, Rosana, Bourboulia, Dimitra, Whitby, Denise, Boshoff, Chris, Patel, Moosa, Ruff, Paul, Bezwoda, Werner R., Retter, Edna, Hale, Martin, and Weiss, Robin
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HERPESVIRUS diseases , *KAPOSI'S sarcoma , *BLACK people , *CANCER , *DISEASES - Abstract
Background: Infection with human herpesvirus 8 (HHV-8) has been consistently linked to Kaposi's sarcoma, but its mode of transmission, association with other cancers, and interaction with the human immunodeficiency virus type 1 (HIV-1) are largely unknown. Methods: Between January 1992 and December 1997, we interviewed 3591 black patients with cancer in Johannesburg and Soweto, South Africa. Blood was tested for antibodies against HIV-1 and HHV-8 in 3344 of the patients. Antibodies against HHV-8 were detected with an indirect immunofluorescence assay. The intensity of the fluorescent signal correlated well with the titers of antibodies (P<0.001). The relations among the presence of anti–HHV-8 antibodies, sociodemographic and behavioral factors, type of cancer, and the presence or absence of coexistent HIV-1 infection were examined with the use of unconditional logistic-regression models. Results: Among the 3293 subjects with cancers other than Kaposi's sarcoma, the standardized seroprevalence of antibodies against HHV-8 was 32 percent, which did not differ significantly from the standardized seroprevalence among black blood donors. Among these 3293 patients, the prevalence of antibodies against HHV-8 increased with increasing age (P<0.001) and an increasing number of sexual partners (P=0.05) and decreased with increasing years of education (P=0.007); it was not strongly associated with HIV-1 infection. Anti–HHV-8 antibodies were more frequent among black than white blood donors (P<0.001). Among the 51 patients with Kaposi's sarcoma, the standardized seroprevalence of antibodies against HHV-8 was 83 percent, significantly higher than the prevalence among those without Kaposi's sarcoma (P<0.001). For 16 other specific types of cancer, including multiple myeloma (108 cases) and prostate cancer (202 cases), the variation in the standardized seroprevalence of antibodies against HHV-8 was not remarkable. At a given intensity of fluorescence of anti–HHV-8 antibodies, Kaposi's sarcoma was more frequent among HIV-1–positive patients than among those who were HIV-1–negative (P<0.001). Conclusions: Among black patients with cancer in South Africa, the seroprevalence of anti–HHV-8 antibodies is high and is specifically associated with Kaposi's sarcoma, particularly at high titers. (N Engl J Med 1999;340:1863-71.) [ABSTRACT FROM AUTHOR]
- Published
- 1999
- Full Text
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