Abstract

We have: observed that p68 RNA helicase acquired substantially higher level of phosphorylation(s) at tyrosine residues in both metastatic cancer cell lines and tissue samples compared to that in non-metastatic cancer cell lines and tissue samples. P68 is not phosphorylated in non-cancerous tissues. We also found that phosphorylation of p68 at tyrosine 593 is required for epithelial-mesenchymal-transition (EMT), a critical event for cancer metastasis. The phosphorylated p68 promotes EMT by facilitating beta-catenin nuclear translocation and activating transcription of Snail gene. Our hypothesis is that the phosphorylated p68 is a new and important regulatory factor that plays important role(s) in promoting EMT and tumor progression/metastasis. The goals of this research proposal are two fold: (1) to gain a comprehensive understanding of the molecular mechanism by which the phospho-p68 promotes EMT, and (2) to extensively test the role of the phospho-p68 in promoting cancer metastasis.
In specific aim 1, we propose experiments to test the role of the p68 phosphorylation in promoting cancer metastasis both in xenograft mice model and in tissue samples from cancer patients.
In specific aim 2, we design experiments to elucidate the mechanism by which the phospho-p68 activates Snail gene transcription. We will test whether the phospho- p68 use its protein-dependent ATPase activity to 'displace'HDAC1 from remodeling and deacetylation complex (NuRD) at Snail promoter. Most cancer-related deaths are the consequence of the cancer metastasis. Although an outline picture about the process of cancer metastasis is emerge, the detailed mechanism is still far beyond fully understanding, especially the cellular factors that contribute to each steps of cancer metastasis.
In specific aim 3, we propose experiments to test whether the phospho-p68 actively 'transports'cytoplasmic beta-catenin to the nucleus. Our study will uncover a new molecular factor that is involved in cancer metastasis. Understanding the functional role of phospho-p68 will ultimately be applied to develop new strategies to the diagnosis/prognosis and treatment for cancer metastasis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118113-04
Application #
7879451
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$219,640
Indirect Cost

  Institution

Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302

  Publications

Turaga, Ravi Chakra; Yin, Lu; Yang, Jenny J et al. (2016) Rational design of a protein that binds integrin ?v?3 outside the ligand binding site. Nat Commun 7:11675
Pu, Fan; Xue, Shenghui; Yang, Jenny J (2016) ProCA1.GRPR: a new imaging agent in cancer detection. Biomark Med 10:449-52
Zhang, Yinwei; Li, Liangwei; Liu, Yuan et al. (2016) PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis. Wound Repair Regen 24:328-36
Pu, Fan; Salarian, Mani; Xue, Shenghui et al. (2016) Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI. Nanoscale 8:12668-82
Xue, Shenghui; Yang, Hua; Qiao, Jingjuan et al. (2015) Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Proc Natl Acad Sci U S A 112:6607-12
Pu, Fan; Qiao, Jingjuan; Xue, Shenghui et al. (2015) GRPR-targeted Protein Contrast Agents for Molecular Imaging of Receptor Expression in Cancers by MRI. Sci Rep 5:16214
Kost, Gina Chun; Yang, Mi Young; Li, Liangwei et al. (2015) A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With ?-Catenin Function Through Y593 Phospho-p68 RNA Helicase. J Cell Biochem 116:1595-601
Li, Liangwei; Zhang, Yinwei; Qiao, Jingjuan et al. (2014) Pyruvate kinase M2 in blood circulation facilitates tumor growth by promoting angiogenesis. J Biol Chem 289:25812-21
Xue, Shenghui; Qiao, Jingjuan; Jiang, Jie et al. (2014) Design of ProCAs (protein-based Gd(3+) MRI contrast agents) with high dose efficiency and capability for molecular imaging of cancer biomarkers. Med Res Rev 34:1070-99
Gao, Xueliang; Wang, Haizhen; Yang, Jenny J et al. (2013) Reciprocal regulation of protein kinase and pyruvate kinase activities of pyruvate kinase M2 by growth signals. J Biol Chem 288:15971-9

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