{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"The Role of Protein Kinase C in Mammalian Target of Rapamycin Signaling and its Therapeutic Implications in Non-Small Cell Lung Cancer","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/11401/76467"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"The mammalian target of rapamycin (mTOR) signaling pathway, which integrates extracellular and intracellular signals, plays a key role in cell metabolism, growth and survival; therefore, the proteins in the signaling pathway must be tightly regulated in order to maintain cellular homeostasis. Conversely, dysregulation of key components of mTOR signaling pathway leads to increased cellular growth and proliferation, which is implicated in many human cancers. Protein kinase C (PKC) is a family of serine/ threonine kinases that regulate many cellular processes including proliferation and cell survival. It has been shown to regulate mTOR signaling in some human cancers. However, the mechanism by which PKC regulates mTOR remains unclear. Recently, studies from our lab have shown that sustained activation of PKC induces robust phosphorylation of p70S6K, a well-known substrate of mTORC1, in a delayed pattern, and this phosphorylation requires classical PKC (cPKC) and phospholipase D (PLD). Importantly, the phosphorylation of p70S6K requires internalization of cPKC and the formation of the cPKC- containing endosomes, a dynamic subset of the slow recycling compartment that depends on PKC and PLD. In addition, we observed that sustained activation of PKC induces mTOR translocation to lysosomes, which appears to require the distinct nPKCs subfamily. Indeed, with PMA treatment, the mTOR- containing lysosomes become very close to the PLD-and PKC- containing endosomes but they remain distinct. These data suggest that sustained activation of PKC activates mTORC1 through a novel and more complicated mechanism. Lastly we found that a subset of non-small cell lung cancer (NSCLC) cell lines which have constitutively active epidermal growth factor receptor (EGFR) tends to have higher protein level of protein kinase c \u03b1 (PKC\u03b1). Interestingly, in these cancer cells, the activation of mTOR is highly dependent on the activity of PKC\u03b1 and PLD, and these cells utilize this pathway for cell survival. These data have important clinical implication as most NSCLC patients develop secondary mutation in EGFR and resistance to treatment with EGFR inhibitors, and our data provide evidence that targeting PKC\u03b1 in mutant EGFR-mediated cancers may be used as second line treatment after patients develop the secondary mutation."},{"label":"dcterms.available","value":"2017-09-20T16:50:21Z"},{"label":"dcterms.contributor","value":"Mao, Cungui"},{"label":"dcterms.creator","value":"Liu, Mengling"},{"label":"dcterms.dateAccepted","value":"2017-09-20T16:50:21Z"},{"label":"dcterms.dateSubmitted","value":"2017-09-20T16:50:21Z"},{"label":"dcterms.description","value":"Department of Molecular and Cellular Biology"},{"label":"dcterms.extent","value":"135 pg."},{"label":"dcterms.format","value":"Monograph"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/11401/76467"},{"label":"dcterms.issued","value":"2016-12-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2017-09-20T16:50:21Z (GMT). No. of bitstreams: 1\nLiu_grad.sunysb_0771E_12696.pdf: 13593916 bytes, checksum: be420cb6fbe9ec1823ba4b0ea0f0aef7 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"Molecular biology"},{"label":"dcterms.title","value":"The Role of Protein Kinase C in Mammalian Target of Rapamycin Signaling and its Therapeutic Implications in Non-Small Cell Lung Cancer"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/16%2F69%2F36%2F166936558621380764631240587345314438539/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/16%2F69%2F36%2F166936558621380764631240587345314438539","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}