The University of Chicago Research Funding

• Principal Investigator: Anning Lin, PhD, Professor, Ben May Department for Cancer Research, Committee on Cancer Biology, Committee on Molecular Medicine/MPMM
• Start Date: July 17, 2009
• Total Award Amount: $316,895 (first year) $316,897 (second year)

Public Health Relevance

The MAP kinase JNK plays a central role in many pathophysiological events and its deregulation has been implicated in numerous human diseases and certain types of cancer. Understanding how TNF-induced JNK activation is selectively regulated by Miz1, a stimulus-specific modulator or regulator (SMOR), may provide significant insights into the integration or “wiring” of the intracellular signaling circuitry that leads to JNK activation in response to a variety of extracellular stimuli and may eventually lead to identification of potential therapeutic targets.

Project Description

The long-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby identifying potential therapeutic targets for prevention and treatment of human diseases. In this proposal, we will study the molecular mechanism by which the zinc finger protein Miz1, a novel stimulus-specific modulators or regulators (SMOR) in the JNK signalsome, selectively regulates TNF-induced JNK activation and the pathophysiological implications of this regulation.

Using multifaceted approaches, we have recently discovered that Miz1 is a novel component of the JNK signalsome and negatively regulates TNF-induced JNK activation and cell death through suppression of TRAF2 K63-linked polyubiquitination. Miz1-mediated inhibition is highly specific, as it inhibits activation of JNK but not other mitogen-activated protein kinases (MAPKs) or Ikappa B kinase (IKK) by TNF and only inhibits JNK activation by TNF but not other known JNK inducers. We hypothesize that Miz1 is a novel SMOR that selectively regulates TNF-induced JNK activation and inflammation and is a potential therapeutic target. This proposal is novel, as it will determine the molecular mechanism by which Miz1 regulates TNF-induced JNK1 activation, to elucidate the molecular mechanism by which Miz1 itself is inactivated by TNF, and to determine the pathophysiological functions of Miz1-mediated inhibition on the TNF signlaing in vivo.

This study will put forward a novel paradigm regarding the molecular mechanism by which the TNF signaling circuitry is integrated and will also provide the rationale in the developing novel strategies for prevention and treatment of inflammation-related human diseases including cancer.

This award is funded under the American Recovery and Reinvestment Act of 2009, NIH Award number: 2R01CA100460-06A1