Regulation of RNA biogenesis for metabolic adaptation of cancer cells
RNA processing and quality control are pivotal nodes of gene expression control during cell fate decision and disease development. The Lee lab’s scientific focus is to reveal signaling and metabolic networks that rewire RNA biogenesis in the context of human cancer. Through proteomic, transcriptomic and metabolomic analysis of mTORC1 (mechanistic target of rapamycin complex 1) pathway, we found that mTORC1 signaling supports metabolic adaptation of cancer cells by enhancing RNA splicing, stability and translation of key metabolic enzymes. Our works shed light on the underlying mechanism of how mTORC1 signaling, activated by oncogenic signals, growth factors and nutrients, controls post-transcriptional RNA biogenesis for cell proliferation and survival, and put forward RNA processing enzymes as therapeutic targets for cancer treatment.
Rewiring of RNA epitranscriptome by metabolic and signaling networks
Chemical modifications of nucleotides, such as methylation, acetylation and deamination, dynamically control DNA and RNA metabolism and gene expression by affecting nucleotide base pairing and recruiting adaptor proteins. Our work revealed physiological functions of ppGpp nucleotide phosphatase in nutrient sensing pathway (Sun*, Lee* et al. Nat Struct Mol Biol, 2010). We are continuing to investigate molecular functions of RNA chemical modifications and their impact on human pathophysiology. Using molecular biological and mass spectrometry analyses, we study 1) how oncogenic signaling and metabolic pathways control chemical modifications of RNA; and 2) how the RNA epitranscriptomic landscapes influence transcriptome and proteome that govern cell growth, survival and differentiation. Our work will uncover new, exciting links between signal transduction, cellular metabolism and the epitranscriptomic landscape of cells and organisms, inspiring novel therapeutic avenues for human diseases.
Gina Lee, PhD (Principal Investigator)
Assistant Professor at UC Irvine School of Medicine. Postdoc in Dr. John Blenis’ lab at Harvard Medical School / Weill Cornell Medicine. PhD in Dr. Jongkyeong Chung’s lab at Korea Advanced Institute of Science and Technology (KAIST) / Seoul National University. BS in Biological Sciences at KAIST.
Recipient of TS alliance, LAM foundation and KSMCB Fellowships, and Tri-institutional Breakout Prize for junior investigators.
Lavina Mathur, MS (Lab manager/Research assistant)
Lavina received her Master of Science in Biotechnology Management from UC Irvine. She is interested in RNA dynamics and metabolism.
Joohwan Kim, PhD (Postdoctoral fellow)
Joohwan studied tumor angiogenesis and microRNA during his PhD at Kangwon National University School of Medicine.
- Park JH, Lee G, Blenis J. Structural insights into the activation of mTORC1 on the lysosomal surface. Trends Biochem Sci. (2020) 45:367-369. (preview)
- Krishnamoorthy GP, Davidson NR, Leach SD, Zhao Z, Lowe SW, Lee G, Landa I, Nagarajah J, Saqcena M, Singh K, Wendel HG, et al. EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov. (2019) 9:264-281.
- Zheng Y, Lin TY, Lee G, Paddock MN, Momb J, Cheng Z, Li Q, Fei DL, Stein BD, Ramsamooj S, Zhang G, Blenis J, Cantley LC. Mitochondrial one-carbon pathway supports cytosolic folate integrity in cancer cells. Cell (2018) 175:1546-1560.
- He L, Gomes AP*, Wang X*, Yoon SO*, Lee G, Nagiec M, Cho S, Chavez A, Islam T, Yu Y, Asara JM, Couvillon A, Kim BY, Blenis J. mTORC1 promotes metabolic reprogramming by suppression of Foxk1 phosphorylation. Mol. Cell (2018) 70:949-960.
- Lee G, Zheng Y*, Cho S*, Jang C, England C, Dempsey JM, Yu Y, Liu X, He L, Cavaliere PM, Chavez A, Zhang E, Isik M, Couvillon A, Dephoure NE, Blackwell TK, Yu JJ, Rabinowitz JD, Cantley LC, Blenis J. Post-transcriptional regulation of de novo lipogenesis by mTORC1-S6K1-SRPK2 signaling. Cell (2017) 171:1545-1558.
- Wada S, Neinast M, Jang C, Ibrahim YH, Lee G, Babu A, Li J, Hoshino A, Rowe GC, Rhee J, Martina JA, Puertollano R, et al. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev. (2016) 30:2551-2564.
- Csibi A*, Lee G*, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, Blenis J. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B dependent control of c-Myc translation. Curr. Biol. (2014) 24:2274-2280.
- Lee G, Blenis J. Akt-ivation of RNA Splicing. Mol. Cell (2014) 53:519-520. (preview)
- Lee G, Liang C, Park G, Jang C, Jung JU*, Chung J*. UVRAG is required for organ rotation by regulating Notch endocytosis in Drosophila. Dev. Biol. (2011) 356:588-597.
- Sun D*, Lee G*, Lee JH*, Kim H, Rhee H, Park S, Kim K, Kim Y, Kim BY, Hong J, Park C, Choy HE, Kim JH, Jeon YH, Chung J. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat. Struct. Mol. Biol. (2010) 17:1188-1194.
- Hyun S*, Lee JH*, Jin H*, Nam JW, Namkoong B, Lee G, Chung J, Kim VN. Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K. Cell (2009) 139:1096-1108.
- Jang C, Lee G, Chung J. LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in Drosophila melanogaster. J. Cell Biol. (2008) 183:11-17.
- Lee G, Chung J. Discrete functions of rictor and raptor in cell growth regulation in Drosophila. Biochem. Biophys. Res. Commun. (2007) 357:1154-1159.
- Complete List: https://www.ncbi.nlm.nih.gov/myncbi/1ZM4OW7RkLl5e/bibliography/public/
We are looking for enthusiastic postdocs, students and research technicians. Those interested in studying RNA signaling & metabolism, please contact firstname.lastname@example.org.