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Clohessy, John

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Clohessy

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Clohessy, John
Author's Publications: search.filters.isAuthorOfPublication.d82f862d-1bed-45f1-9a32-26411d07b7a3

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    Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism
    (Nature Publishing Group UK, 2018) Chen, Ming; Wan, Lixin; Zhang, Jiangwen; Zhang, Jinfang; Mendez, Lourdes; Clohessy, John; Berry, Kelsey; Victor, Joshua; Yin, Qing; Zhu, Yuan; Wei, Wenyi; Pandolfi, Pier Paolo
    The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1α/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1α acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1α into PML nuclear bodies, hence repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1α/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.
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    Role of aberrant PI3K pathway activation in gallbladder tumorigenesis
    (Impact Journals LLC, 2014) Lunardi, Andrea; Webster, Kaitlyn A.; Papa, Antonella; Padmani, Bhavik; Clohessy, John; Bronson, Roderick; Pandolfi, Pier Paolo
    The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to “trunkular” mutations.
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    A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
    (2013) Lunardi, Andrea; Ala, Ugo; Epping, Mirjam T.; Salmena, Leonardo; Clohessy, John; Webster, Kaitlyn A.; Wang, Guocan; Mazzucchelli, Roberta; Bianconi, Maristella; Stack, Edward C.; Lis, Rosina; Patnaik, Akash; Cantley, Lewis C.; Bubley, Glenn; Cordon-Cardo, Carlos; Gerald, William L.; Montironi, Rodolfo; Signoretti, Sabina; Loda, Massimo; Nardella, Caterina; Pandolfi, Pier Paolo
    Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten-loss driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed upon deletion of either Trp53 or Lrf together with Pten, leading to the development of castration resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1-XIAP/SRD5A1 as a predictive and actionable signature for CRPC. Importantly, we show that combined inhibition of XIAP, SRD5A1, and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates stratification of patients and the development of tailored and innovative therapeutic treatments.
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    The RNA Binding Protein ESRP1 Fine-Tunes the Expression of Pluripotency-Related Factors in Mouse Embryonic Stem Cells
    (Public Library of Science, 2013) Fagoonee, Sharmila; Bearzi, Claudia; Di Cunto, Ferdinando; Clohessy, John; Rizzi, Roberto; Reschke, Markus; Tolosano, Emanuela; Provero, Paolo; Pandolfi, Pier Paolo; Silengo, Lorenzo; Altruda, Fiorella
    In pluripotent stem cells, there is increasing evidence for crosstalk between post-transcriptional and transcriptional networks, offering multifold steps at which pluripotency can be controlled. In addition to well-studied transcription factors, chromatin modifiers and miRNAs, RNA-binding proteins are emerging as fundamental players in pluripotency regulation. Here, we report a new role for the RNA-binding protein ESRP1 in the control of pluripotency. Knockdown of Esrp1 in mouse embryonic stem cells induces, other than the well-documented epithelial to mesenchymal-like state, also an increase in expression of the core transcription factors Oct4, Nanog and Sox2, thereby enhancing self-renewal of these cells. Esrp1-depleted embryonic stem cells displayed impaired early differentiation in vitro and formed larger teratomas in vivo when compared to control embryonic stem cells. We also show that ESRP1 binds to Oct4 and Sox2 mRNAs and decreases their polysomal loading. ESRP1 thus acts as a physiological regulator of the finely-tuned balance between self-renewal and commitment to a restricted developmental fate. Importantly, both mouse and human epithelial stem cells highly express ESRP1, pinpointing the importance of this RNA-binding protein in stem cell biology.
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    Dual DNA and Protein Tagging of Open Chromatin Unveils Dynamics of Epigenomic Landscapes in Leukemia
    (Springer Science and Business Media LLC, 2021-03-01) Lee, Jonathan D.; Paulo, Joao; Posey, Ryan R.; Mugoni, Vera; Kong, Nikki; Cheloni, Giulia; Lee, Yu-Ru; Slack, Frank; Tenen, Daniel; Clohessy, John; Gygi, Steven; Pandolfi, Pier Paolo
    The architecture of chromatin specifies eukaryotic cell identity by controlling transcription factor access to sites of gene regulation. Here we describe a dual transposase/peroxidase approach, integrative DNA And Protein Tagging (iDAPT), which detects both DNA (iDAPT-seq) and protein (iDAPT-MS) associated with accessible regions of chromatin. In addition to direct identification of bound transcription factors, iDAPT enables the inference of their gene regulatory networks, protein interactors, and regulation of chromatin accessibility. We applied iDAPT to profile the epigenomic consequences of granulocytic differentiation of acute promyelocytic leukemia, yielding previously undescribed mechanistic insights with potential therapeutic implications. Our findings demonstrate the power of iDAPT as a discovery platform for both the dynamic epigenomic landscapes and their transcription factor components associated with biological phenomena and disease.
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    Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer
    (John Wiley and Sons Inc., 2018) Ali, Azhar; Levantini, Elena; Teo, Jun Ting; Goggi, Julian; Clohessy, John; Wu, Chan Shuo; Chen, Leilei; Yang, Henry; Krishnan, Indira; Kocher, Olivier; Zhang, Junyan; Soo, Ross A; Bhakoo, Kishore; Chin, Tan Min; Tenen, Daniel
    Abstract Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo. Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients.