Gabriela Chiosis: Chemical Biology Approach to Investigate Regulation of Pathogenic Stress by the Molecular Chaperone Machinery

Molecular chaperones are ubiquitously expressed proteins with wide-ranging functions in the folding and cellular translocation of a variety of proteins (1,2). Whereas these house-keeping functions are well recognized and have been the subject of intense investigation, it is now becoming clearer that chaperones are also co-opted in pathogenic cells to carry out disease-specific specialized roles. It is now believed that in pathogenic systems, chaperones abet transformation and allow for the blossoming of the disease phenotype (3-5).

Research in my laboratory is aimed at investigating and bringing answers to several questions:

What are the transformation specific roles taken on by chaperones?
Can we understand and differentiate the disease abetting roles of chaperones from their house keeping functions?
Can we discover pharmacologic modulators of the disease specific chaperone function and translate them into novel therapeutics?
Can we investigate and understand molecular lesions intrinsic to each disease phenotype through our understanding of the molecular chaperones?

Didelot C, Lanneau D, Brunet M, Bouchot A, Cartier J, Jacquel A, Ducoroy P, Cathelin S, Decologne N, Chiosis G, Dubrez-Daloz L, Solary E, Garrido C. Interaction of heat-shock protein 90 beta isoform (HSP90 beta) with cellular inhibitor of apoptosis 1 (c-IAP1) is required for cell differentiation. Cell Death Differ. 2008 May;15(5):859-66. Epub 2008 Feb 1.

Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick K, Aguirre J, Wu N, Greengard P, Chiosis G. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9511-6. Epub 2007 May 21.

Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW, Chiosis G. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol. 2007 Aug;3(8):498-507. Epub 2007 Jul 1

Goeckeler JL, Petruso AP, Aguirre J, Clement CC, Chiosis G, Brodsky JL. The yeast Hsp110, Sse1p, exhibits high-affinity peptide binding. FEBS Lett. 2008 Jun 5.

Wang L, Xie C, Greggio E, Parisiadou L, Shim H, Sun L, Chandran J, Lin X, Lai C, Yang WJ, Moore DJ, Dawson TM, Dawson VL, Chiosis G, Cookson MR, Cai H. The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci. 2008 Mar 26;28(13):3384-91.

Targeting Hsp90: small-molecule inhibitors and their clinical development. Taldone T, Gozman A, Maharaj R, Chiosis G. Curr Opin Pharmacol. 2008 Aug;8(4):370-4.

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73.

Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Rieker R, Bergmann F, Schirmacher P, Mayer M, Chiosis G, Kern MA. Hepatology. 2009 Jul;50(1):102-12.

A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas.Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA, Mallik A, Robles AI, Walling J, Varticovski L, Shaknovich R, Bhalla KN, Chiosis G, Melnick A.Nat Med. 2009 Dec;15(12):1369-76.

Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab. Holland JP, Caldas-Lopes E, Divilov V, Longo VA, Taldone T, Zatorska D, Chiosis G, Lewis JS. PLoS One. 2010 Jan 25;5(1):e8859.