10 results on '"Bourboulia, Dimitra"'
Search Results
2. Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer.
- Author
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Backe, Sarah J., Sager, Rebecca A., Meluni, Katherine A., Woodford, Mark R., Bourboulia, Dimitra, and Mollapour, Mehdi
- Subjects
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]
- Published
- 2022
- Full Text
- View/download PDF
3. TRAP1 Chaperones the Metabolic Switch in Cancer.
- Author
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Wengert, Laura A., Backe, Sarah J., Bourboulia, Dimitra, Mollapour, Mehdi, and Woodford, Mark R.
- Subjects
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]
- Published
- 2022
- Full Text
- View/download PDF
4. Decrypting the chaperone code.
- Author
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Truman, Andrew W., Bourboulia, Dimitra, and Mollapour, Mehdi
- Subjects
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SCIENTIFIC ability , *GTPASE-activating protein , *HEAT shock factors , *RAS proteins , *ALLOSTERIC regulation , *MUTANT proteins , *HEAT shock proteins , *MOLECULAR chaperones - Published
- 2021
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5. Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90–Client Interactions.
- Author
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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]
- Published
- 2020
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6. Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients.
- Author
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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]
- Published
- 2017
- Full Text
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7. Structural and functional basis of protein phosphatase 5 substrate specificity.
- Author
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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]
- Published
- 2016
- Full Text
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8. Asymmetric Hsp90 N Domain SUMOylation Recruits Aha1 and ATP-Competitive Inhibitors.
- Author
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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
- Subjects
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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]
- Published
- 2014
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9. MP39-02 OVEREXPRESSION OF MPS1 IN CLEAR CELL RENAL CELL CARCINOMA (CCRCC) CONFERS TUMOR SELECTIVITY ON HEAT SHOCK PROTEIN-90 (HSP90) INHIBITORS.
- Author
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Abouelleil, Mourad, Dunn, Diana, Woodford, Mark, Jensen, Sandra, Chehab, Mahmoud, Madala, Alosh, Caza, Tiffany, Landas, Steve, Stetler-Stevenson, William G., Neckers, Len, Bourboulia, Dimitra, Bratslavsky, Gennady, and Mollapour, Mehdi
- Subjects
RENAL cell carcinoma ,GENETIC overexpression ,HEAT shock proteins ,ANEUPLOIDY ,NEOPLASTIC cell transformation ,GENETIC mutation ,GENETICS - Published
- 2015
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10. Swe1Wee1-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function
- Author
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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
- Subjects
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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]
- Published
- 2010
- Full Text
- View/download PDF
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