| dc.identifier.uri | http://hdl.handle.net/11401/76485 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | The DNA damage response (DDR) is a complex and interconnected signaling network that dictates whether a cell repairs itself and survives or is damaged beyond repair and eliminated; therefore the proteins in this network must be tightly regulated in order to ensure genomic integrity. Conversely, mutational or epigenetic inactivation of DDR components leads to genomic instability, a hallmark of cancer. Indeed there is a high frequency of DDR defects in human cancers of which mutations in the DDR effector and tumor suppressor protein p53 are the best characterized and occur in greater than 50% of all human cancers. Interestingly, a novel DDR pathway has emerged termed the CHK1-Suppressed (CS) pathway that is activated by inhibition or loss of the cell cycle kinase CHK1, leading to an apoptotic response to DNA damage in the presence of mutant p53 that is mediated by the protease Caspase 2. Although the functions of the CS-pathway have been probed through pharmacological inhibition and siRNA knockdown it remains unclear whether and how CHK1 inhibition can be regulated endogenously. Recently, we characterized the first endogenous activation of the CS-pathway, demonstrating that upon DNA damage wild type p53 acts an endogenous regulator of CHK1 levels that modulates Caspase 2 activation and ultimately controls cell fate. Moreover, we demonstrate that CHK1 levels persist in response to DNA damage in mutant p53 cancer cells, leading to CHK1-mediated activation of the pro-survival transcription factor NF-κB and induction of a pro-inflammatory response that is abrogated by loss or inhibition of CHK1. These data constitute a novel role for CHK1 in response to DNA damage outside of the cell cycle in regulating inflammation. Lastly we identify the lipid kinase Sphingosine Kinase 1 (SK1), whose kinase activity produces the pro-survival lipid mediator Sphingosine 1-Phosphate (S1P) as the first identified effector of the CS-pathway; whereby activation of the CS-pathway leads to SK1 proteolysis and decreases in cellular S1P levels in response to DNA damage. These data have important clinical applications as many CHK1 inhibitors are in clinical trials and our data provide evidence that targeting CHK1 in mutant p53-mediated cancers may abrogate NF-κB and SK1 signaling both of which are associated with increased cellular survival and chemoresistance. | |
| dcterms.abstract | The DNA damage response (DDR) is a complex and interconnected signaling network that dictates whether a cell repairs itself and survives or is damaged beyond repair and eliminated; therefore the proteins in this network must be tightly regulated in order to ensure genomic integrity. Conversely, mutational or epigenetic inactivation of DDR components leads to genomic instability, a hallmark of cancer. Indeed there is a high frequency of DDR defects in human cancers of which mutations in the DDR effector and tumor suppressor protein p53 are the best characterized and occur in greater than 50% of all human cancers. Interestingly, a novel DDR pathway has emerged termed the CHK1-Suppressed (CS) pathway that is activated by inhibition or loss of the cell cycle kinase CHK1, leading to an apoptotic response to DNA damage in the presence of mutant p53 that is mediated by the protease Caspase 2. Although the functions of the CS-pathway have been probed through pharmacological inhibition and siRNA knockdown it remains unclear whether and how CHK1 inhibition can be regulated endogenously. Recently, we characterized the first endogenous activation of the CS-pathway, demonstrating that upon DNA damage wild type p53 acts an endogenous regulator of CHK1 levels that modulates Caspase 2 activation and ultimately controls cell fate. Moreover, we demonstrate that CHK1 levels persist in response to DNA damage in mutant p53 cancer cells, leading to CHK1-mediated activation of the pro-survival transcription factor NF-κB and induction of a pro-inflammatory response that is abrogated by loss or inhibition of CHK1. These data constitute a novel role for CHK1 in response to DNA damage outside of the cell cycle in regulating inflammation. Lastly we identify the lipid kinase Sphingosine Kinase 1 (SK1), whose kinase activity produces the pro-survival lipid mediator Sphingosine 1-Phosphate (S1P) as the first identified effector of the CS-pathway; whereby activation of the CS-pathway leads to SK1 proteolysis and decreases in cellular S1P levels in response to DNA damage. These data have important clinical applications as many CHK1 inhibitors are in clinical trials and our data provide evidence that targeting CHK1 in mutant p53-mediated cancers may abrogate NF-κB and SK1 signaling both of which are associated with increased cellular survival and chemoresistance. | |
| dcterms.available | 2017-09-20T16:50:24Z | |
| dcterms.contributor | Shroyer, Kenneth | en_US |
| dcterms.contributor | Obeid, Lina | en_US |
| dcterms.contributor | Hannun, Yusuf | en_US |
| dcterms.contributor | Frohman, Michael | en_US |
| dcterms.contributor | Bhaduri-McIntosh, Sumita. | en_US |
| dcterms.creator | Carroll, Brittany | |
| dcterms.dateAccepted | 2017-09-20T16:50:24Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:24Z | |
| dcterms.description | Department of Molecular and Cellular Biology. | en_US |
| dcterms.extent | 179 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/76485 | |
| dcterms.issued | 2015-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:24Z (GMT). No. of bitstreams: 1
Carroll_grad.sunysb_0771E_12383.pdf: 3326409 bytes, checksum: a3ee2ae3430c712cf9c04d61a16a75fe (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | CHK1, DNA damage response, p53, sphingolipids | |
| dcterms.subject | Molecular biology | |
| dcterms.title | The DNA Damage Response: p53 Regulation of the CHK1-Suppressed Pathway and Sphingolipid Metabolism | |
| dcterms.type | Dissertation | |
