Arun Kumar Trivedi, Ph.D.
Senior Principal Scientist, Cancer Biology
Primary focus of our lab is to investigate cellular machinery that mediate
protein homeostasis
Research interest of our lab focuses to understand mechanisms underlying breast cancer pathogenesis and impaired differentiation in Acute Myeloid leukemia along following lines:
(a) Identification of deregulated E3 ubiquitin ligases and Deubiquitinases (DUBs) and their impact on stability of key regulatory proteins (oncogenes, tumor suppressor and TFs) implicated in disease manifestations.
E3 ubiquitin ligases (E3s) regulate a variety of biologic processes by timely ubiquitination and degradation of many cell cycle and apoptosis- regulatory proteins. These E3 ubiquitin ligases transfer activated ubiquitin moieties in the ubiquitination process from Ubiquitin E2 ligases to the substrates that are destined to be degraded. Finally, these polyubiquitinated protein substrates are degraded by proteasomes where Deubiquitinases (DUBs) remove ubiquitin moieties (that becomes available as free pool for E3s) prior to their degradation by proteasomes. Since E3s timely regulate protein turnover, their controlled regulation is crucial for cell functioning. Due to their common deregulation and a role in the development of cancers, targeting the ubiquitin cascade (Fig. 1) in cancer therapeutics has emerged as a promising approach. In fact, FDA approval of general proteasome inhibitor bortezomib in the treatment of multiple myeloma has established ubiquitin-protasome system as a potential therapeutic target in cancer therapy. Our Lab focuses to understand mechanisms leading to deregulation of key E3s viz. FBW7, SKP2 and E6AP (at mRNA as well as protein levels), identify their substrates and elucidate how these pathways can be targeted for therapeutic benefit. Our research has identified several new substrates of FBW7 as well as E6AP not known earlier. Currently, we are engaged in identifying how FBW7 is regulated at promoter levels.
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