The Hedgehog (Hh) signaling pathway plays important roles in development and in cancer. The Hh ligand, which activates the pathway, is derived from the autoprocessing of the Hh precursor protein. Hh autoprocessing is at the very beginning of the Hh signaling pathway and likely plays crucial roles in both physiology and disease. However, the basic mechanisms of Hh autoprocessing and its role in diseases are poorly understood. Using an interdisciplinary approach, we will define the catalytic mechanism of Hh autoprocessing with atomic resolution and study two novel roles for Hh autoprocessing in prostate cancer. We will first define the catalytic mechanism of Hh autoprocessing with solution NMR; we will then study a new mechanism of tumorigenesis involving zinc deficiency and Hh activation in prostate cancer; lastly we will establish Hh autoprocessing of cancer drugs as a novel means of drug resistance in prostate cancer.

Public Health Relevance

Hedgehog signaling is implicated in many cancers. We will study novel mechanism of how Hedgehog signaling pathway is activated by zinc imbalance and Hedgehog autoprocessing in prostate cancer and a novel mechanism of drug resistance in prostate cancer through Hedgehog autoprocessing. The data from the study will contribute to fundamental understanding of the pathogenic mechanism of cancers, and point to new directions in cancer diagnosis and drug discovery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA206592-02
Application #
9402595
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Knowlton, John R
Project Start
2016-12-15
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rensselaer Polytechnic Institute
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
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Minteer, Christopher J; Siegart, Nicolle M; Colelli, Kathryn M et al. (2017) Intein-Promoted Cyclization of Aspartic Acid Flanking the Intein Leads to Atypical N-Terminal Cleavage. Biochemistry 56:1042-1050
Zwarycz, Allison S; Fossat, Martin; Akanyeti, Otar et al. (2017) V67L Mutation Fills an Internal Cavity To Stabilize RecA Mtu Intein. Biochemistry 56:2715-2722
Xie, Jian; Owen, Timothy; Xia, Ke et al. (2016) A Single Aspartate Coordinates Two Catalytic Steps in Hedgehog Autoprocessing. J Am Chem Soc 138:10806-9
Bordeau, Brandon M; Ciulla, Daniel A; Callahan, Brian P (2016) Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer. ChemMedChem 11:1983-6