Defective cell cycle regulation leads to genomic instability and ultimately cancer development. The E3 ubiquitin ligase APC/Cdh1 is a major regulator of cell cycle progression and has been implicated in DNA damage repair and tumor suppression, although its exact roles remain unclear. In this proposal, we will explore the interaction of Cdh1 with multiple major tumor suppressor and oncogenic pathways frequently altered in human cancers to define the novel functions as well as regulatory mechanisms for Cdh1. We previously reported that Cdh1 targets the Skp2 oncoprotein for proteolysis;our preliminary data showed that the PI3K/Akt pathway protected Skp2 from Cdh1-mediated destruction.
In Aim 1, we will utilize both genetic and biochemical approaches to reveal the underlying molecular mechanisms by which Akt1 controls Skp2 abundance and cellular localization. The proposed studies will provide a novel mechanism for Skp2 overexpression in human cancers. It will also advance our knowledge of how specific kinase signaling cascades influence proteolysis governed by the APC/Cdh1 complex, and provide the rationale for developing Akt1-specific inhibitors as potent anti-cancer drugs.
In Aim 2, we will define the molecular mechanisms by which loss of Cdh1 activates the p53 and Rb pathways, and their contribution to Cdh1 loss-induced premature senescence. We found that by controlling Claspin destruction, Cdh1 regulates Chk1 activity and further influences the p53 pathway, implicating a role for Cdh1 in DNA damage repair. We also found that Cdh1 could affect Rb/E2F1 function. As a result, depletion of Cdh1 in primary human fibroblasts led to the onset of premature senescence by activating both the p53 and Rb pathways. Inactivation of other tumor suppressors, including PTEN and VHL, also induced premature senescence, which has been proposed as a built-in fail-safe mechanism against cancer development. Our proposed work in Aim 2 will provide the possible underlying molecular mechanism for the less frequently observed Cdh1 loss in tumor cells, which could further imply Cdh1 loss as a late event in tumor development. Lastly, our proposal explores how Cdh1 itself is regulated. Our preliminary data indicated that the Mdm2 oncoprotein controls the stability of Cdh1 in late G1/S phase. This finding extends our understanding of the interplay between the Cdh1 and p53/Mdm2 pathways, and provides further evidence that the functions of major cell cycle regulators are interwoven to achieve synergized effects. Our proposed work in Aim 3 will provide a novel regulatory mechanism for Cdh1 stability control, thus uncovering another layer of mechanism for the oncogenic function of Mdm2 and supporting the use of Mdm2 inhibitors for cancer treatment. Altogether, these studies will significantly expand our current knowledge of the important functions of Cdh1 outside its classic role in cell cycle control by providing insight into how Cdh1 integrates into the network of major tumor suppressor (p53 and Rb) and oncogene (Akt and Mdm2) pathways to not only govern cell cycle progression, but also maintain genomic stability and participate in tumor suppression.
APC/Cdh1, whose function has been implicated in DNA damage repair and tumor suppression, is a critical regulator that governs cell cycle progression. However, the underlying molecular mechanisms are unknown. We plan to study the interplay between Cdh1 and major tumor suppressors (p53 and Rb) and oncogenic (Akt and Mdm2) pathways, thus uncovering the regulatory functions of Cdh1 in cell cycle checkpoint, DNA damage repair and tumor suppression. These studies will provide valuable insight into how Cdh1 integrates into the network of tumor suppressor/oncogene pathways to maintain genomic stability and suppress tumor development, and will also provide the rationale for developing specific Akt1 and Mdm2 inhibitors as potent anti-cancer reagents.
|Wan, Lixin; Xu, Kexin; Wei, Yongkun et al. (2018) Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function. Mol Cell 69:279-291.e5|
|Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95|
|Clement, Emilie; Inuzuka, Hiroyuki; Nihira, Naoe T et al. (2018) Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors. Sci Signal 11:|
|Huang, Li-Yu; Zhao, Junjie; Chen, Hao et al. (2018) SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis. Nat Commun 9:3569|
|Wang, Xu; Cao, Wei; Zhang, Jianjun et al. (2017) A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination. EMBO J 36:1243-1260|
|Wan, Lixin; Chen, Ming; Cao, Juxiang et al. (2017) The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function. Cancer Discov 7:424-441|
|Wu, Fei; Dai, Xiangpeng; Gan, Wenjian et al. (2017) Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation. Cancer Lett 385:207-214|
|Dai, Xiangpeng; Gan, Wenjian; Li, Xiaoning et al. (2017) Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med 23:1063-1071|
|Wang, Bin; Jie, Zuliang; Joo, Donghyun et al. (2017) TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. Nature 545:365-369|
|Shimizu, Kouhei; Fukushima, Hidefumi; Ogura, Kohei et al. (2017) The SCF?-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis. Sci Signal 10:|
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