Browsing by Author "Naidu, Samisubbu"

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    The role of PTEN in human cancer
    (2015) Gendron, Jaimie Michelle; Mayo, Lindsey D.; Goebl, Mark G.; Harrington, Maureen A.; Naidu, Samisubbu
    Phosphatase and tensin homolog, PTEN, is a key tumor suppressor. Mutation of PTEN is associated with both sporadic cancers and a cluster of familial cancer predisposition syndromes called PTEN hamaratoma syndromes. These germline mutations span the length of the PTEN gene with a mutational hot spot localized in exon 5. This exon encodes the catalytic domain of PTEN, which is critical for its tumor suppressor activity. PTEN function is most commonly attributed to lipid phosphatase activity on Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) that leads to inhibition of a cascade with downstream pro-survival effectors including Akt, but PTEN also has phosphatase activity on a small number of proteins. Recently, a mutation, G129E, has been described as a gain of function (GOF) mutation in PTEN knockin mice. This mutant only retains protein phosphatase activity while it completely lacks lipid phosphatase activity. Collectively (in the mouse and in vitro studies), there is no clear mechanism to explain the GOF nature of this mutant. Understanding how mutants of PTEN function in the cells to provide a growth advantage will provide insight into what pathway to therapeutically target. Our central hypothesis is that mutations of PTEN promote tumorigenesis through gain of function activities that result in cell cycle progression. We will determine the signaling pathways that are affected by the gain of function mutant PTEN G129E to better understand the mechanism by which mutants of PTEN confer a growth advantage.
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    SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy
    (Springer Nature, 2023-03-09) Liang, Shuxin; Bao, Changlei; Yang, Zi; Liu, Shiyun; Sun, Yanan; Cao, Weitao; Wang, Ting; Schwantes-An, Tae-Hwi; Choy, John S.; Naidu, Samisubbu; Luo, Ang; Yin, Wenguang; Black, Stephen M.; Wang, Jian; Desai, Ankit A.; Tang, Haiyang; Medical and Molecular Genetics, School of Medicine
    Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation (pNF-κB) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.