I. Research in my lab has focused on understanding the molecular mechanisms underlying the central role of the heat shock protein Hsp72 in cancer. In cancer cells Hsp72 is often expressed at very high levels, and its expression correlates with the aggressiveness of tumors. Recently we have found that Hsp72 regulates early stages of tumorigenesis. Indeed, Hsp72 can control signaling pathways initiated by major oncogenes, resulting in avoiding growth inhibition and facilitating cell proliferation and transformation.
Our research addresses several questions:
(1) How Hsp72 keeps the p53 pathway activated by PIK3CA oncogene under control?
(2) How Hsp72 prevents cell senescence activated by Her2 oncogene.
II. In a distinct project we study a process of aggregation of abnormal polypeptides. When chaperone and protein degradation machineries fail to handle abnormal proteins, they aggregate and cause cell toxicity, which may give rise to various neurological disorders. As the last line of defense, a special machinery has evolved that transports these toxic aggregates to a centrosome location via microtubules, which leads to relieve of toxicity. The resulting non-toxic single large aggregate is called aggresome. Previously we have established a yeast model to study aggregation and toxicity of the disease-causing polypeptides with expanded polyglutamine domain. Now, using both yeast and mammalian systems, we are dissecting the pathway of aggresome formation.
Our current research within this project uses genetics and biochemical approaches to addresses the following questions:
(1) What cellular components are involved in aggresome formation?
(2) What signaling pathways control aggresome formation?
Vladimir Gabai – Research Assistant Professor
Julia Yaglom – Research Assistant Professor
Anatoli Meriin – Instructor
Yongmei Wang – Visiting Researcher
Lee do H, Sherman MY, Goldberg AL. The requirements of yeast Hsp70 of SSA family for the ubiquitin-dependent degradation of short-lived and abnormal proteins. Biochem Biophys Res Commun. 2016 Jun 17; 475(1):100-6. PMID: 27178214.
Zaarur N, Xu X, Lestienne P, Meriin AB, McComb M, Costello CE, Newnam GP, Ganti R, Romanova NV, Shanmugasundaram M, Silva ST, Bandeiras TM, Matias PM, Lobachev KS, Lednev IK, Chernoff YO, Sherman MY. RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils. EMBO J. 2015 Sep 14; 34(18):2363-82. PMID: 26303906.
Sabbieti MG, Agas D, Capitani M, Marchetti L, Concetti A, Vullo C, Catone G, Gabai V, Shifrin V, Sherman MY, Shneider A, Venanzi FM. Plasmid DNA-coding p62 as a bone effective anti-inflammatory/anabolic agent. Oncotarget. 2015 Feb 28; 6(6):3590-9. PMID: 25668818.
Gong J, Weng D, Eguchi T, Murshid A, Sherman MY, Song B, Calderwood SK. Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. Oncogene. 2015 Oct; 34(43):5460-71. PMID: 25659585.
Li X, Colvin T, Rauch JN, Acosta-Alvear D, Kampmann M, Dunyak B, Hann B, Aftab BT, Murnane M, Cho M, Walter P, Weissman JS, Sherman MY, Gestwicki JE. Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer. Mol Cancer Ther. 2015 Mar; 14(3):642-8. PMID: 25564440.
Gabai V, Venanzi FM, Bagashova E, Rud O, Mariotti F, Vullo C, Catone G, Sherman MY, Concetti A, Chursov A, Latanova A, Shcherbinina V, Shifrin V, Shneider A. Pilot study of p62 DNA vaccine in dogs with mammary tumors. Oncotarget. 2014 Dec 30; 5(24):12803-10. PMID: 25296974.
Sherman MY, Gabai VL. Hsp70 in cancer: back to the future. Oncogene. 2015 Aug 6; 34(32):4153-61. PMID: 25347739.
Yaglom JA, McFarland C, Mirny L, Sherman MY. Oncogene-triggered suppression of DNA repair leads to DNA instability in cancer. Oncotarget. 2014 Sep 30; 5(18):8367-78. PMID: 25252808.
Colvin TA, Gabai VL, Gong J, Calderwood SK, Li H, Gummuluru S, Matchuk ON, Smirnova SG, Orlova NV, Zamulaeva IA, Garcia-Marcos M, Li X, Young ZT, Rauch JN, Gestwicki JE, Takayama S, Sherman MY. Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Res. 2014 Sep 1; 74(17):4731-40. PMID: 24994713.
Colvin TA, Gabai VL, Sherman MY. Proteotoxicity is not the reason for the dependence of cancer cells on the major chaperone Hsp70. Cell Cycle. 2014; 13(14):2306-10. PMID: 24911412.
Complete list can be found at BU Profiles