NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. NEDD4-1 plays an important role in tumorigenesis. Although it has been suggested that NEDD4-1 functions as an oncogenic protein by facilitation of Akt activation, the molecular mechanisms by which NEDD4-1 activates Akt remain largely unknown. We found that NEDD4-1 activates Akt via regulation of IGF-1R signaling. Strikingly, we also found that activation of Akt by NEDD4-1 is negatively regulated by replication protein A (RPA), a single strand DNA (ssDNA) binding protein which is generally believed to play a critical role in DNA metabolism. Thus, we are proposing a study to test the central hypothesis that NEDD4-1 plays a role in cell proliferation via activation of IGF-1R signaling and this pathway is inhibited by RPA. Therefore, growth of cells overexpressing NEDD4-1 is specifically suppressed by IGF-1R inhibition through IGF-1R antibody and/or RPA. Three interrelated specific aims are proposed to test our hypothesis.
Aim 1 will identify the role of NEDD4-1 in cell proliferation via regulation of IGF-1R signaling.
Aim 2 will delineate how NEDD4-1 dependent IGF-1R signaling is regulated by RPA.
Aim 3 will determine the antitumor activity of blocking IGF-1R signaling in cells over-expressing NEDD4-1. We anticipate to (1) define the molecular mechanisms by which NEDD4-1 promotes cell proliferation via regulation of IGF-1R signaling;(2) identify a novel function of RPA in suppression of IGF-1R signaling via interaction with NEDD4-1;(3) find that the growth of cancer cells over-expressing NEDD4-1 can be specifically targeted by IGF-1R inhibition through RPA and/or IGF-1R antibody. The expected results will fundamentally advance our understanding of the molecular mechanism underlying NEDD4-1 associated cancer development. In addition, identification of a novel function of RPA in suppression of IGF-1R signaling will facilitate the development of novel drugs targeting NEDD4-1 or IGF-1R. Moreover, the expected result will improve guidance for cancer treatment plans based on better predictions of tumor response to IGR-1R inhibition by identification of cancer patients with NEDD4-1 over-expression.
NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. Our proposed studies are aimed at delineating the role of NEDD4-1 in cell proliferation and cancer therapy via regulation of IGF-1 receptor (IGF-1R). The successful completion of this work would (1) advance cell signaling field by providing mechanistic insight into NEDD4-1 associated cancer development;(2) facilitate the identification and development of biomarkers and drug targets in human cancer;(3) provide new guidelines and novel approaches for treating cancer patients with NEDD4-1 over-expression.
|Zhang, Yao; Lai, Jinzhi; Du, Zhanwen et al. (2016) Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress. Oncotarget 7:34688-702|
|Graziano, S; Johnston, R; Deng, O et al. (2016) Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence. Oncogene :|
|Wang, Y; Deng, O; Feng, Z et al. (2016) RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. Oncogene 35:1363-72|
|Xiong, Xiahui; Du, Zhanwen; Wang, Ying et al. (2015) 53BP1 promotes microhomology-mediated end-joining in G1-phase cells. Nucleic Acids Res 43:1659-70|
|Kan, Charlene; Zhang, Junran (2015) BRCA1 Mutation: A Predictive Marker for Radiation Therapy? Int J Radiat Oncol Biol Phys 93:281-93|
|Wang, Z; Xu, D; Ding, H-F et al. (2015) Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene 34:4975-84|
|Krishnamurthy, Nirmala; Liu, Lili; Xiong, Xiahui et al. (2015) Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells. Cancer Biol Ther 16:518-27|
|Li, Linhao; Li, Haishan; Garzel, Brandy et al. (2015) SLC13A5 is a novel transcriptional target of the pregnane X receptor and sensitizes drug-induced steatosis in human liver. Mol Pharmacol 87:674-82|
|Chatterjee, Payel; Choudhary, Gaurav S; Alswillah, Turkeyah et al. (2015) The TMPRSS2-ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition. Mol Cancer Ther 14:1896-906|
|Cui, Hongmei; Guo, Mingxiong; Xu, Dong et al. (2015) The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nat Commun 6:6752|
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