CONTACT

Lab Accomplishments

Major contributions:

 

  • The early days for personal medicine | 1-5
     

  • Rewired signaling nodes in cancer | 6-10
     

  • Ubiquitin ligases control fundamental cellular processes (i.e. hypoxia, UPR), with implications for pathologies including cancer | 11-20, 24, 25

Identified mutant oncogenes in pre-neoplastic lesions and bodily fluids.

  • Established the enriched PCR method in 1991 | 1
     

  • Identified mutant Ras alleles in normal-appearing colonic tissues and lavage/sputum from smokers | 2-5

Defined rewired oncogenic signaling pathways.

  • Cross-talk between ERK and JNK signaling in melanoma | 6
     

  • Signals elicited by DNA breaks that activate stress kinases | 7
     

  • Redox (GSTp) control of stress kinases | 8
     

  • Ubiquitin-based signaling controls stress-activated transcription | 9,10

Demonstrated how ubiquitin ligases control fundamental cellular processes.

  • Hypoxia (in controlling prolyl hydroxylase (PHD1, PHD3) stability | 11
     

  • UPR (unfolded protein response) – specifically, showed that Siah1/2 controls ATF4 signaling, with implication for ischemia | 12
     

  • Mitochondrial dynamics – Siah2 controls mitochondrial fission, with implications for myocardial infarction and aging | 13
     

  • Duration of stress signaling (TRAF2/JNK) controlled by Siah2 | 14
     

  • Ik-B and b-catenin stability controlled by b-TRCP ubiquitin ligase | 15

Established the roles of ubiquitin ligases in cancer development and chemoresistance.

  • Siah2 controls melanoma development and metastasis | 16
     

  • Development of neuroendocrine prostate cancers requires Siah2-dependent HIF signaling | 17
     

  • Hormone-refractory prostate tumors require Siah2, which controls androgen receptor activity | 18
     

  • RNF5 control of glutamine carrier proteins determines breast cancer responsiveness to taxenes | 19#
     

  • Melanoma resistance to BRAF inhibitors is RNF125/JAK1 dependent | 20#

Oncogenic vs tumor suppressor signaling depends on subcellular localization of key factors or changes in genomic organization.

  • PKCe phosphorylation of ATF2 determines its subcellular localization and its oncogenic (nuclear) or tumor suppressor (cytosolic) activity | 21
     

  • An ATF2 splice variant lacking transcriptional capacity serves as a super-oncogene | 22
     

  • ERK-dependent cytoplasmic accumulation of hnRNPK limits mRNA translation | 23

Select Relevant Literature

  1. Kahn, S.M., Jiang, W., Culbertson, T.A., Weinstein, I.B. Williams, G.M., Ronai, Z. Rapid and sensitive nonradioactive detection of mutant K-ras genes via ‘enriched’ PCR amplification. Oncogene 6:1079-83, 1991.
     

  2. Minamoto, T., Ronai, Z., Yamashita, N., Ochiai, A., Sugimura, T., Mai, M., Esumi, H. Detection of Ki-ras mutation in non-neoplastic mucosa of Japanese patients with colorectal cancers. Int J Oncol 4:397-401, 1994.
     

  3. Tobi, M., Luo, F.C., Ronai, Z. Detection of K-ras mutation in colonic effluent samples from patients without evidence for colorectal carcinoma. J Natl Cancer Inst 86:1007-10, 1994.
     

  4. Ronai, Z., Minamoto, T., Butler, R., Tobi, M., Luo, F-Q., Zang, E., Esumi, H., Sigimura, T. Sampling method as a key factor in identifying K-ras oncogene mutations in preneoplastic colorectal lesions. Cancer Detect Prev 19:512-7, 1995.
     

  5. Minamoto, T., Yamashita, N., Ochiai, A.A., Mai, M., Sugimura, T., Ronai, Z., Esumi, H. Mutant K-ras in normal appearing mucosa of colorectal cancer patients: implication for a biomarker of colorectal tumorigenesis. Cancer 75:1520-6, 1995.
     

  6. Lopez-Bergami, P., Huang, C., Goydos, J. S., Yip, D., Bar-Eli, M., Herlyn, M., Smalley, K. S. M., Mahale, A., Eroshkin, A., Aaronson, S., Ronai, Z. Re-wired ERK-JNK signaling pathways in melanoma. Cancer Cell 11:447-60, 2007.
     

  7. Adler, V., Fuchs, S.Y., Kim, J., Kraft, A., King, M.P., Pelling, J., Ronai, Z. jun-NH2-terminal kinase activation mediated by UV-induced DNA lesions in melanoma and fibroblast cells. Cell Growth Diff 6:1437-46, 1995.
     

  8. Adler, V., Yin, Z., Fuchs, S.Y., Benezra, M., Rosario, L., Tew, K.D., Pincus, M.R., Sardana, M., Henderson, C.J., Wolf, C.R., Davis, R. Ronai, Z. Regulation of JNK signaling by GSTp. EMBO J 18:1321-34, 1999.
     

  9. Fuchs, S.Y., Dolan, L.R., Davis, R., Ronai, Z. Phosphorylation dependent targeting of c-Jun ubiquitination by Jun N-kinase. Oncogene 13:1531-5, 1996.
     

  10. Fuchs, S.Y, Adler, V., Buschmann, T., Minamoto, T., Wu, X., Jones, S.N., Ronai, Z. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev 12:2658-63, 1998.
     

  11. Nakayama, K., Frew, I.J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P.B., Bowtell, D.D., Ronai, Z. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 117:941-52, 2004.
     

  12. Scortegagna, M., Kim, H., Li, J.L., Yao, H., Brill, L.M., Han, J., Lau, E., Bowtell, D., Haddad, G., Kaufman, R.J., Ronai, Z.A. Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS Genet. 10:e1004348, 2014.
     

  13. Kim, H., Scimia, M.C., Wilkinson, D., Trelles, R.D., Wood, M.R., Bowtell, D., Dillin, A., Mercola, M., Ronai, Z.A. Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Mol Cell 44:532-44, 2011.
     

  14. Habelhah, H., Frew, I., Laine, A., Janes, P., Relaix, F., Sassoon D., Bowtell, D., Ronai, Z. Stress-induced decrease in TRAF2 stability is mediated by Siah2. EMBO J 21:5756-65, 2002.
     

  15. Fuchs, S.Y., Chen, A., Xiong, Y., Pan, Z.Q., Ronai, Z. HOS, a human homologue of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. Oncogene 18:2039-46, 1999.

  16. Qi, J., Nakayama, K., Gaitonde, S., Goydos, J.S., Krajewski, S., Eroshkin, A., Bar-Sagi, D., Bowtell, D., Ronai, Z. The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways. Proc Natl Acad Sci USA 105:16713-8, 2008.
     

  17. Qi, J., Nakayama, K., Cardiff, R.D., Borowsky, A.D., Kaul K., Williams R., Krajewski, S., Mercola, D., Carpenter, P.M., Bowtell, D., Ronai, Z.A. Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell 18:23-38, 2010.
     

  18. Qi, J., Tripathi, M., Mishra, R., Sahgal, N., Fazli, L., Ettinger, S., Placzek, W.J., Claps, G., Chung, L.W., Bowtell, D., Gleave, M., Bhowmick, N., Ronai, Z.A. The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity. Cancer Cell 23:332-46, 2013.
     

  19. Jeon, Y.J., Khelifa, S., Ratnikov, B., Scott, D.A., Feng, Y., Parisi, F., Ruller, C., Lau, E., Kim, H., Brill, L.M., Jiang, T., Rimm, D., Cardiff, R., Mills, G.B., Smith, J.W., Osterman, A.L., Kluger, Y., Ronai, Z.A., Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell 27:354-69, 2015.
     

  20. Kim, H., Frederick, D.T., Feng, Y., Brill, L., Samuels, Y., Hayward, N.K., Halaban, R., Perlina, A., Zhang, T., Brown, K.M., Flaherty, K.T., Ronai, Z.A. Downregulation of the ubiquitin ligase RNF125 underlies resistance of melanoma cells to BRAF inhibitors via JAK1 deregulation. Cell Reports 11:1458-73, 2015.
     

  21. Lau, E., Kluger, H., Varsano, T., Lee, K.Y., Scheffler, I., Rimm, D.L., Ideker, T., Ronai, Z.A. PKCe promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell 148:543-55, 2012.
     

  22. Claps G. Cheli Y. Zhang T. Scortegagna M. Lau E. Kim H. Qi J. Li J.-L. James B. Dzung A. Levesque M.P. Dummer R. Hayward N.K. Bosenberg M. Brown K.M. Ronai Z.A.  A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis. Cell Reports 15(9):1884-92, 2016.
     

  23. Habelhah, H., Shah, K., Hunag, L., Ostareck-Lederer. A., Burlingame, A.L., Shokat, K.M., Hentze, M.W., Ronai, Z. ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation. Nat Cell Biol 3:325-30, 2001. 
     

  24. Li Y, Tinoco R, Elmén L, Segota I, Xian Y, Fujita Y, Sahu A, Zarecki R, Marie K, Feng Y, Khateb A, Frederick DT, Ashkenazi SK, Kim H, Perez EG, Day CP, Segura Muñoz RS, Schmaltz R, Yooseph S, Tam MA, Zhang T, Avitan-Hersh E, Tzur L, Roizman S, Boyango I, Bar-Sela G, Orian A, Kaufman RJ, Bosenberg M, Goding CR, Baaten B, Levesque MP, Dummer R, Brown K, Merlino G, Ruppin E, Flaherty K, Ramer-Tait A, Long T, Peterson SN, Bradley LM, Ronai ZA. Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5-/- mice. Nat Commun. 10(1):1492, 2019.
     

  25. Fujita Y, Khateb A, Li Y, Tinoco R, Zhang T, Bar-Yoseph H, Tam MA, Chowers Y, Sabo E, Gerassy Vainberg S, Starosvetsky E, James B, Brown K, Shen-Orr SS, Bradley LM, Tessier PA, Ronai ZA. Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis. Cell Rep. 24(12):3296-3311, 2018.

# notes studies that resulted or expected to lead to clinical trials

  • multi-center clinical trial in BCa treated with combination of paclitaxel and glutaminase inhibitor

    | based on 19
     

  • Evaluation of JAK1 inhibitor in melanoma resistance to BRAF inhibitor therapy, recruiting to clinical trial | based on 20
     

  • Development of novel antibodies to S100A8, RNF5 substrate, as means to limit intestinal inflammation disorders | based on 25