Dr. Ronai's laboratory is working to understand the regulation and function of mammalian stress-response signaling pathways.
Dr. Ronai earned his Ph.D. in Tumor Immunology from the Hebrew University of Jerusalem, Israel in 1985.
A role for ATF2 in regulating MITF and melanoma development.
Shah M, Bhoumik A, Goel V, Dewing A, Breitwieser W, Kluger H, Krajewski S, Krajewska M, Dehart J, Lau E, Kallenberg DM, Jeong H, Eroshkin A, Bennett DC, Chin L, Bosenberg M, Jones N, Ronai ZA
PLoS Genet. 2010;6(12):e1001258
Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors.
Qi J, Nakayama K, Cardiff RD, Borowsky AD, Kaul K, Williams R, Krajewski S, Mercola D, Carpenter PM, Bowtell D, Ronai ZA
Cancer Cell. 2010 Jul 13;18(1):23-38
Interplay between Cdh1 and JNK activity during the cell cycle.
Gutierrez GJ, Tsuji T, Chen M, Jiang W, Ronai ZA
Nat Cell Biol. 2010 Jul;12(7):686-95
The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways.
Qi J, Nakayama K, Gaitonde S, Goydos JS, Krajewski S, Eroshkin A, Bar-Sagi D, Bowtell D, Ronai Z
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16713-8
The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis.
Delaunay A, Bromberg KD, Hayashi Y, Mirabella M, Burch D, Kirkwood B, Serra C, Malicdan MC, Mizisin AP, Morosetti R, Broccolini A, Guo LT, Jones SN, Lira SA, Puri PL, Shelton GD, Ronai Z
PLoS One. 2008;3(2):e1609
Suppressor role of activating transcription factor 2 (ATF2) in skin cancer.
Bhoumik A, Fichtman B, Derossi C, Breitwieser W, Kluger HM, Davis S, Subtil A, Meltzer P, Krajewski S, Jones N, Ronai Z
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1674-9
Rewired ERK-JNK signaling pathways in melanoma.
Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S, Ronai Z
Cancer Cell. 2007 May;11(5):447-60
RACK1 mediates activation of JNK by protein kinase C [corrected].
López-Bergami P, Habelhah H, Bhoumik A, Zhang W, Wang LH, Ronai Z
Mol Cell. 2005 Aug 5;19(3):309-20
ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.
Bhoumik A, Takahashi S, Breitweiser W, Shiloh Y, Jones N, Ronai Z
Mol Cell. 2005 May 27;18(5):577-87
Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia.
Nakayama K, Frew IJ, Hagensen M, Skals M, Habelhah H, Bhoumik A, Kadoya T, Erdjument-Bromage H, Tempst P, Frappell PB, Bowtell DD, Ronai Z
Cell. 2004 Jun 25;117(7):941-52
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The state of melanoma: challenges and opportunities.
Merlino G, Herlyn M, Fisher DE, Bastian BC, Flaherty KT, Davies MA, Wargo JA, Curiel-Lewandrowski C, Weber MJ, Leachman SA, Soengas MS, McMahon M, Harbour JW, Swetter SM, Aplin AE, Atkins MB, Bosenberg MW, Dummer R, Gershenwald JE, Halpern AC, Herlyn D, Karakousis GC, Kirkwood JM, Krauthammer M, Lo RS, Long GV, McArthur G, Ribas A, Schuchter L, Sosman JA, Smalley KS, Steeg P, Thomas NE, Tsao H, Tueting T, Weeraratna A, Xu G, Lomax R, Martin A, Silverstein S, Turnham T, Ronai ZA
Pigment Cell Melanoma Res. 2016 Apr 17;
Ze'ev Ronai's Research Focus
Cancer, Prostate Cancer, Skin Cancer and Melanoma
Watch Dr. Ronai describe his research
Our research is directed towards understanding the regulation and function of the signaling pathways which play a central role in the mammalian stress response. In particular, we are interested in ubiquitin ligases and protein kinases that cooperate in the regulation of important cellular functions, including hypoxia, ER stress and cell cycle.
Accordingly, we focus on (1) the ubiquitin ligase Siah2, which our lab has discovered as important regulator of prolyl hydroxylase and hypoxia, (2) the ubiquitin ligase RNF5 which is important in ER-stress response, and (3) the kinase JNK in context of cell cycle control, re-wired control in melanoma and impact on ER stress. Studies are also devoted to understanding of the transcription factor ATF2, which was discovered in our lab to play important role in DNA damage and ATM response.
Ze'ev Ronai's Research Report
E3 Ligase Siah and the Hypoxia Response
Our work on the E3 protein ligase Siah led to the identification of a novel layer in regulation of the cellular hypoxia response. We identified prolyl hydroxylases 1 and 3 (PHD1/3) as Siah substrates, in particular, in hypoxia (Nakayama et al., Cell., 2004). These findings establishes the mechanism underlying stabilization of HIF1 hypoxia (2-7% oxygen), a level that allows retention of sufficient oxygen for activity of PHDs. These findings also point to the existence of other regulatory components in mild hypoxia, a physiologic state whose role is central in development, differentiation and organ maintenance. More recent studies have pointed out to the role of p38 kinase in the phosphorylation and subcellular localization of Siah2 under hypoxia conditions (Khurana et al., JBC, 2006), and for the assembly of PHD complexes under hypoxia, as a mechanism that affect their activity and susceptibility to Siah2-mediated degradation (Nakayama et al., Biochem. J. 2007). Ongoing studies using Siah2 KO mice points to the importance of Siah2 in tumor development as well as in its metastatic capacity. These findings identify that in melanoma model Siah2 effect on PHD and consequently HIF1a affects the ability of the tumor to metastasize, without affecting its tumorigenic capacity. We have identified that Siah2 effect on Sprouty 2, a negative regulator of Ras signaling pathway, is responsible for tumorigenicity. Thus, Siah2 affect tumor and metastasis in melanoma model via regulation of distinct substrates and regulatory pathways – the Ras signaling for tumor formation (via Sprouty 2) and the HIF signaling (via PHD3) for metastatic capacity. Ongoing studies elucidate the role of Siah2 in prostate tumor model, highlighting novel mechanistic insights into Siah2 regulation and importance in development and progression of different tumor types. The notion that Siah2 is playing such important role in tumor development and progression also prompted screen for inhibitors that would specifically affect this ubiquitin ligase.
E3 Ligase RNF5 and its Associated Protein JAMP – in ER-stress Response
RNF5 is a RING finger E3 ligase which was shown in previous studies from our lab to be involved in regulation of cytoskeletal protein stability as well as subcellular localization. RNF5’s effect on key cytoskeletal proteins affects cell adhesion and motility and is expected to affect tumorigenicity and metastasis capacity, especially in tumors in which it is deregulated. Initial studies revealed role of RNF5 in breast cancer cells organization and proliferation (Broomberg et al., Cancer Res. 2007). Our studies on RNF5 include work in C. elegans, KO mice as well as transgenic mice, which provide important systems that complement our cell biology and biochemical studies. Using transgenic mouse model we discovered that overexpression of RNF5 results in muscular disorder that resembles inclusion Body Myocytis (IBM) – a prevalent muscle disorder in older people which has been associated with extensive ER stress. Our mouse model (rtTA-MCK-RNF5) is the first to allow studying this muscular disorder in mice (Delaunay et al., Plos One, 2008). Ongoing studies point to the role of RNF5 in protein trafficking and degradation, primarily those localized within the ER compartment.
Further, among RNF5-associated proteins is JAMP, a JNK-associated transmembrane protein that affects JNK signaling, which is localized in the ER membrane and emerges as a novel receptor for proteasomes. JAMP recruits proteasomes following ER stress and facilitates the degradation of malfolded proteins (Tcherpakov et al., Mol Biol Cell. 2008). The implications of RNF5 and JAMP activities for ER-stress as well as pathological conditions are currently under investigation using corresponding KO and Tg mouse models.
JNK – Novel Insights into Regulation and Function
Recent studies from our lab identified that the level of JNK activity is regulated by PKC, via the adaptor protein RACK1 (Bergami-Lopez, Mol Cell., 2005). The importance of PKC to JNK signaling is expected to also impact cytoskeletal organization and RNA translation, given the involvement of RACK1 in these processes, aspects that are currently under investigation in our lab. Importantly, JNK activation is subject to changes in pathological cases as in human tumors. Our recent studies in melanoma revealed the mechanism for re-wiring of signal transduction pathways in this tumor type where ERK feeds onto the activation of JNK through upregulation of c-Jun, with concomitant activation of RACK1 – to feed forward PKC-JNK signaling (Bergami Lopez, Cancer Cell, 2007). The implications of such re-wiring are further investigated.
In parallel studies we have identified undisclosed link between JNK and cell cycle control, an aspect that is currently studied, and is expected to shed important new light on the regulation and function of this important protein kinase.
ATF2 - Transcription Factor and DNA Damage Response Protein
Among JNK substrates is ATF2. Our studies have demonstrated the role of the transcription factor ATF2 in the development and notorious resistance of melanomas to treatment. Ongoing studies evaluate chemical compounds for their ability to inhibit melanoma growth and metastatic potential, based on former studies with a 10 or 50aa peptide driven from this transcription factor. Preclinical testing are ongoing with a subset of derivatives which exhibit promising results (Abbas et al., Clin Cancer Res. 2007). Using a mouse model for melanoma we now explore the role of ATF2 in melanoma development using a genetic model. Initial results reveal that lack of ATF2 cause marked inhibition in melanoma development. Mechanisms underlying ATF2 role in melanoma development are currently investigated.
Studies from our lab have also shown that ATF2 is an ATM substrate and that ATF2 functions in the DNA damage response by affecting DSB foci formation and cell cycle checkpoint control. The mechanisms underlying ATF2's contribution to the DNA damage response appear to involve components important for chromatin organization. The implications for ATF2 in tumor development and DNA damage response are currently under investigation using KO and KI mouse models. Using KI ATF2 mouse (where ATF2 phosphorylation sites by ATM were mutated, we identify high sensitivity to IR, resembling ATM mice. Mechanisms underlying ATF2 role in radiation resistance and cell cycle control are currently studied.
About Ze'ev Ronai
Ze’ev Ronai earned his Ph.D. in Tumor Immunology from the Hebrew University of Jerusalem, Israel in 1985. He trained as a postdoctoral fellow in molecular biology and viral carcinogenesis at Columbia University in New York. Dr. Ronai established the Molecular Carcinogenesis Program at the American Health Foundation in 1989 while serving as Adjunct Professor at the New York Medical College in Valhalla, New York. In 1997, Dr. Ronai joined the Ruttenberg Cancer Center at Mount Sinai School of Medicine in New York as Professor, with joint appointments in the Departments of Gene Therapy, Biochemistry, and Pharmacology. Dr. Ronai joined Sanford-Burnham Medical Research Institute in 2004 as Director of the Institute’s Signal Transduction Program.