PNCs are structurally linked to the nucleoli, and they assemble and disassemble in concert with nucleoli through the cell cycle. It is highly enriched with newly synthesized pol III RNA and is dependent upon continuous pol III transcription. The PNC forms in metastatically capable cells and the assembly of the PNC is not simply the results of over expression of the PNC components. Over the last funding cycle (3.5 years), using RNase MRP RNA (RMRP) as an example, we have found that PNC contains a novel RMRP containing complex. The complex contains PTB, CUGBP, RMRP, and other unknown factors, and is large, pelleting at the bottom of a 5-40% glycerol gradient. Using a high resolution light microscopy (OMX), we found that RMRP-PTB-CUGB closely colocalize at the PNC. However, RMRP at the PNC does not colocalize with newly synthesized RNA, suggesting the RNP may not represent the post transcriptional processing of nascent RMRP. In addition, we found that the PNC is associated with unknown DNA loci. These findings lead to our current working model. Unknown RNPs become nucleated upon specific DNA loci, most likely a pol III gene(s), and regulates their expression in PNC containing cells. The regulation can be at the levels of DNA or RNA, or both. We propose three complementary aims to test this hypothesis and to investigate the structure and function of the PNC. We will identify the components of the novel RMRP-PTB-CUGBP complex and the functional relevance of this complex to the PNC and cellular activities. We will identify the PNC associated DNA loci and will dissect the relationship between the novel RNPs and the expression of the loci. The results of these experiments will not only provide the necessary foundation to the future understanding of the structure and function of the PNC and malignancy, but will also reveal uncharacterized function of highly conserved RMRP.
The perinucleolar compartment (PNC) is a nuclear structure forming in cancer cells that are capable of metastasis. To understand the structure and function of the PNC, we propose to identify its molecular components and analyze their function in and out of the PNC during normal and cancerous conditions.
|Frankowski, Kevin J; Wang, Chen; Patnaik, Samarjit et al. (2018) Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis. Sci Transl Med 10:|
|Liu, Yanning; Lou, Guohua; Norton, John T et al. (2017) 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib. FASEB J 31:5453-5465|
|Wang, Chen; Huang, Sui (2017) Drug Development Against Metastatic Cancers. Yale J Biol Med 90:119-123|
|Kuramoto, Kenta; Wang, Nan; Fan, Yuying et al. (2016) Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids. Autophagy 12:1460-71|
|Kim, Dong-Hyun; Li, Weiguo; Chen, Jeane et al. (2016) Multimodal Imaging of Nanocomposite Microspheres for Transcatheter Intra-Arterial Drug Delivery to Liver Tumors. Sci Rep 6:29653|
|Wang, Chen; Huang, Sui (2014) Nuclear function of Alus. Nucleus 5:131-7|
|Wen, Yiping; Wang, Chen; Huang, Sui (2013) The perinucleolar compartment associates with malignancy. Front Biol (Beijing) 8:|
|Norton, John T; Huang, Sui (2013) The perinucleolar compartment: RNA metabolism and cancer. Cancer Treat Res 158:139-52|
|Fitzpatrick, Terry; Huang, Sui (2012) 3'-UTR-located inverted Alu repeats facilitate mRNA translational repression and stress granule accumulation. Nucleus 3:359-69|
|Liu, Yanning; Norton, John T; Witschi, Mark A et al. (2011) Methoxyethylamino-numonafide is an efficacious and minimally toxic amonafide derivative in murine models of human cancer. Neoplasia 13:453-60|
Showing the most recent 10 out of 17 publications