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Characterizing Putative Driver Event...

Davis, Matthew Joseph.

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Characterizing Putative Driver Events in Cancer: Fast-Cycling with RAC1 and Oncogenic Stabilization of a Dominant-Negative CBL Mutation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Characterizing Putative Driver Events in Cancer: Fast-Cycling with RAC1 and Oncogenic Stabilization of a Dominant-Negative CBL Mutation./
作者:	Davis, Matthew Joseph.
面頁冊數:	155 p.
附註:	Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.
Contained By:	Dissertation Abstracts International76-11B(E).
標題:	Genetics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3663464
ISBN:	9781321935721

Characterizing Putative Driver Events in Cancer: Fast-Cycling with RAC1 and Oncogenic Stabilization of a Dominant-Negative CBL Mutation.
Davis, Matthew Joseph.

Characterizing Putative Driver Events in Cancer: Fast-Cycling with RAC1 and Oncogenic Stabilization of a Dominant-Negative CBL Mutation. - 155 p.

Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.

Thesis (Ph.D.)--Yale University, 2015.

This item is not available from ProQuest Dissertations & Theses.

It is well understood that cancer is a disease of the genome. Large second-generation genomic cataloguing efforts have proven useful in identifying a constellation of cancer associated mutations in numerous genes whose pattern have helped stratify patient population treatment, aid in diagnoses and understand basic tumor biology. However, as genomic instability is one of the 'hallmarks of cancer' questions of cause and effect are understandably important. Accordingly, cancer associated genes are broadly designated as 'drivers,' genes that contribute to the cancers progression, and 'passengers,' genes that are not vital to cancers progression. Thus, it is important prioritize putative cancer 'driver' genes for specific biochemical function.

ISBN: 9781321935721Subjects--Topical Terms:

530508
Genetics.

Characterizing Putative Driver Events in Cancer: Fast-Cycling with RAC1 and Oncogenic Stabilization of a Dominant-Negative CBL Mutation.
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245 1 0 $a Characterizing Putative Driver Events in Cancer: Fast-Cycling with RAC1 and Oncogenic Stabilization of a Dominant-Negative CBL Mutation.
300 $a 155 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.
500 $a Adviser: Joseph Schlessinger.
502 $a Thesis (Ph.D.)--Yale University, 2015.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a It is well understood that cancer is a disease of the genome. Large second-generation genomic cataloguing efforts have proven useful in identifying a constellation of cancer associated mutations in numerous genes whose pattern have helped stratify patient population treatment, aid in diagnoses and understand basic tumor biology. However, as genomic instability is one of the 'hallmarks of cancer' questions of cause and effect are understandably important. Accordingly, cancer associated genes are broadly designated as 'drivers,' genes that contribute to the cancers progression, and 'passengers,' genes that are not vital to cancers progression. Thus, it is important prioritize putative cancer 'driver' genes for specific biochemical function.
520 $a Cancer subtypes including melanoma and lung adenocarcinoma (LUAD) reveal the importance of identifying and more importantly understanding the 'driver' events underlying their respective progression. Specifically, gain-offunction 'driver' genes including BRAF and EGFR in melanoma and LUAD respectively have been targeted pharmacologically leading to great clinical impact. Consequently, these successes have fueled fervent efforts to discover and understand other potentially tractable 'driver' events in these devastating diseases. Therefore I have focused my investigations on the identification and functional validation of putative 'driver' events, specifically a recurrent point mutation in RAC1 identified in melanoma and a recurrent splice-variant in CBL identified in LUAD.
520 $a RAC1 is a small, Ras-related GTPase that was recently reported to harbor a recurrent UV-induced signature mutation in melanoma, resulting in substitution of P29 to serine (RAC1P29S), ranking this the third most frequently occurring gain-offunction mutation in melanoma. Although the Ras-family GTPases are mutated in about 30% of all cancers, mutations in the Rho family GTPases have rarely been observed. In this study, we demonstrate that unlike oncogenic Ras proteins, which are primarily activated by mutations that eliminate GTPase activity, the activated melanoma RAC1P29S protein maintains intrinsic GTP hydrolysis and is spontaneously activated by substantially increased inherent GDP/GTP nucleotide exchange. Determination and comparison of crystal structures for activated RAC1 GTPases suggest that RAC1F28L--a known spontaneously activated RAC1 mutant--and RAC1P29S are self-activated in distinct fashions. Moreover, the mechanism of RAC1P29S and RAC1F28L activation differs from the common oncogenic mutations found in Ras-like GTPases that abrogate GTP hydrolysis. The melanoma RAC1P29S gain-of-function point mutation therefore represents a previously undescribed class of cancer-related GTPase activity.
520 $a CBL is a multidomain adaptor protein endowed with E3 ubiquitin ligase activity and prominently involved in the negative regulation of numerous protein tyrosine kinases (PTKs) including receptor tyrosine kinases (RTKs) like EGFR and MET. Through a collaborative whole exome-sequencing (WES) project of LUAD samples it was determined that CBL accumulates somatic mutations. Furthermore, recurrent mutations were found in canonical splice sites surrounding exon 8 of CBL (both upstream and downstream), which are known to cause exon-skipping leading to the expression of a protein that lacks the 44 residues encompassing exon 8 (CBLDelta8). Exon 8 encodes a portion of the linker region and RING domain of CBL, which are responsible for E3 ligase activity. Thus it was hypothesized that CBLDelta8 would not be able to ubiquitinate protein substrates and perhaps allow for potentiation of certain RTK signaling. Furthermore, as the EGFR signaling cascade is of significant interest in LUAD we suggest that patients harboring certain mutant CBL proteins may benefit from EGFR targeted inhibition. In live cancer-derived cells I show that CBLDelta8 acts in a dominant-negative fashion where it is unable to properly ubiquintate EGFR allowing for abrogated degradation and prolonged activation post ligand stimulation. However, in untransformed cell lines including CBL -/- mouse embryonic fibroblasts (MEFs) it was shown that CBLDelta8 protein stability is compromised via constitutive proteosomal degradation not allowing for the mutant to exert its dominant-negative function on EGFR signaling. I suggest that the CBLDelta8 mutant requires the oncogenic cell state in order to act as an oncogene while in the normal untransformed cellular state the protein will act as a null allele.
520 $a Overall I have utilized a variety in vitro biochemical and cellular assays to functionally characterize potential novel `driver' events in two major cancer subtypes. Both RAC1 P29S and CBLDelta8 are novel in function and provide interesting insight into the broad array of mutation and their functionality in cancer.
590 $a School code: 0265.
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650 4 $a Cellular biology. $3 3172791
650 4 $a Biochemistry. $3 518028
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