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Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA

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    Enter Ronai Lab

    ATF2 - a HLH bZIP transcription factor mediates its transcriptional functions upon its heterodimerization with other members of the bZIP family, as primarily demonstrated for c-Jun. For its transcriptional function, ATF2 needs to be phosphorylated by JNK or p38, on N-terminal residues. We found that ATF2 is also subject to modification by ATM (and possibly other members of the PIKK family), whereby it is recruited to DNA damage repair foci (MRN complex) within a few minutes after exposure to DNA damage. ATF2 phosphorylation by ATM occurs on its C-terminal end and is independent of JNK/p38 activities. This study was published in the journal Molecular Cell in 2005.
    Control of p53 on translationally active polysomes. JNK phosphorylation of p53 occurring on polysomes causes the dissociation of Ubc13 from p53, enabling p53 multimerization and transcriptional activation.
    RNF5 ubiquitin ligase controls stability of glutamine carrier proteins, defining glutamine uptake and sensitivity of breast cancer to ER stress inducing therapies (paclitaxel)
    The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions. Read more (Cell, 2012)
    ERK, which is upregulated in melanoma due to mutations in BRAF or NRAS, drives activation of c-Jun transcription and stability, driving c-Jun via ERK in addition to the JNK signaling pathways. Cancer Cell 2007.
    Siah2 ubiquitin ligase controls the formation of neuroendocrine prostate tumors by regulation of HIF1a availability to form transcriptional complex with FOXA2, resulting in the activation of SOX9, HES6, JMJD1a, PLOD2.
    Siah2 ubiquitin ligase controls the stability of prolyl hydroxylase 1 and 3, defining the stability of HIF1a and hypoxia, under physiological hypoxia (4-6% O2).
    RNF5 ubiquitin ligase controls UPR signaling in intestinal epithelial cells, with concomitant effect on gut microbiota composition and activation of anti-tumor immunity
    RNF5 limits levels of S100A8 in intestinal epithelial cells, and thus controls intestinal inflammation (IBD like phenotypes).
    Siah2 ubiquitin ligase controls stability of AKAP121 regulating mitochondrial fission, with implications on heart infract
    Transcriptionally inactive ATF2 (spliced form) functions as super oncogene, drives melanoma development only in the presence of BRAF mutant.
    Translational Reprogramming Marks Adaptation to Asparagine Restriction in Cancer; Nature Cell Biology In press; In this study we unveil a previously unknown axis of adaptation to asparagine deprivation, which provides the basis for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches.
    This study outline how one can convert “cold” tumors that do not respond to immune checkpoint therapy to a “hot” ones which do respond. The work of Hyungsoo Kim in the lab led to the identification of immune signaling pathways that are controlled by the protein methyl transferase PRMT5. PRMT5 was found to inhibit cGAS/STING signaling, contributing to innate immunity, and the expression of NLRC5, which controls antigen presentation, defining recognition by the immune system. Thus, PRMT5 inhibition blocked one of the major tumor escape phenotypes - tumor immune evasion - enabling immune checkpoint therapies. Indeed, PD1 antibodies combined with PRMT5 inhibition, effectively eliminated melanomas, which were otherwise not responding to such therapy. Given that PRMT5 inhibitors are FDA approved, we hope that our finding will catalyze new clinical trials for treatment of “cold tumors”.
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