Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis, thereby preventing cellular expansion under such conditions. The goal of this proposal is to determine the role of the endoplasmic reticulum stress response/Unfolded Protein Response (UPR) in sensing limitations in glucose availability, and thereby facilitating cellular adaptation. PERK, one of three proximal signal transducers of the UPR, plays a central role in mediating cell fate decisions;this kinase has recently been demonstrated to function in the potentiation of tumor growth and survival. Central to our understanding of PERK-dependent survival is dissecting the significance of PERK pro-survival signaling through ATF4 versus PERK-dependent apoptotic signals through the induction of CHOP. Critically, how pro-survival signals are balanced with the induction of the pro-apoptotic transcription factor, CHOP, has remained poorly understood for over a decade. Our preliminary work suggests an overarching hypothesis that temporal regulation of miR- 211 coordinates cellular adaptation with apoptosis in cells exposed to endoplasmic reticulum stress. To test this hypothesis we will 1) determine the mechanisms of ER stress-dependent induction of miR-211 accumulation;2) elucidate the mechanism(s) that regulate miR-211 stability;and 3) determine the role of miR-211 in tumorigenesis. These studies will provide critical new insight into the mechanisms whereby the PERK protein kinase regulates cell homeostasis in response to stress. There are obvious points of cross- talk between this proposal and Project 2 which focuses on how the UPR antagonizes myc induced apoptosis and potentiates tumor cell adaptation. Through collaboration with Project 2, we will assess the role of m|R- 211 as a mediator of cell growth and survival in myc-dependent tumorigenesis. Project 1 intersects with Project 3 through common interests on how PERK regulates IFNAR1, the IFNAR1 E3 ligase and IFNAR1 signaling during tumorigenesis. Through collaboration with Project 3, we will detrmine how miR-211 regulates IFNAR1 regulation during ER stress and tumorigenesis as well as assess miR-211 regulation of downstream interferon signaling. The.findings steming from the work proposed herein will provide a foundation for the design of novel anti-cancer therpeutics.

Public Health Relevance

Recent work has revealed that inactivation of PERK promotes tumor progression, providing support for the development of small molecule inhibitors of PERK for cancer treatment. While these studies provide clear biological support for such approaches, our understanding of how PERK regulates cell survival versus ' apoptosis following oncogenic insult is limited. The work described in this project will delineate molecular mechanisms whereby PERK regulates the temporal onset of apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA165997-02
Application #
8754466
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bu, Yiwen; Diehl, J Alan (2016) PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development. J Cell Physiol 231:2088-96
Xia, Chuan; Vijayan, Madhuvanthi; Pritzl, Curtis J et al. (2016) Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1. J Virol 90:2403-17
Gui, Jun; Gober, Michael; Yang, Xiaoping et al. (2016) Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation. J Invest Dermatol 136:1990-2002
Zhang, Kangjian; Yin, Xiao-Fei; Yang, Yuan-Qin et al. (2016) A potent in vivo anti-tumor efficacy of novel recombinant type I interferon. Clin Cancer Res :
Xu, Zhenhua; Bu, Yiwen; Chitnis, Nilesh et al. (2016) miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. Nat Commun 7:11422
Katlinskaya, Yuliya V; Katlinski, Kanstantsin V; Yu, Qiujing et al. (2016) Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression. Cell Rep 15:171-80
Bu, Yiwen; Diehl, J Alan (2016) Stressing out melanoma with an anti-GRP78 compound. Pigment Cell Melanoma Res 29:490-1
Katlinskaya, Yuliya V; Katlinski, Kanstantsin V; Lasri, Audrey et al. (2016) Type I Interferons Control Proliferation and Function of the Intestinal Epithelium. Mol Cell Biol 36:1124-35
Davar, Diwakar; Fuchs, Serge Y; Kirkwood, John M (2016) BRAF Inhibitors and IFNα: Plus, Minus, or Indeterminate? J Natl Cancer Inst 108:
Yu, Qiujing; Zhao, Bin; Gui, Jun et al. (2015) Type I interferons mediate pancreatic toxicities of PERK inhibition. Proc Natl Acad Sci U S A 112:15420-5

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