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BaxDelta2: From Functional Domains to Cancer Correlation
Başlık:
BaxDelta2: From Functional Domains to Cancer Correlation
Yazar:
Manas Nunez, Adriana, author.
ISBN:
9780438124448
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (115 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Jialing Xiang Committee members: Andrew Howard; Oscar Juarez; Kenneth Tichauer; Jialing Xiang.
Özet:
BaxDelta2 is a functional pro-apoptotic Bax isoform, originally identified in cancer patients with microsatellite instability. Here we performed an extensive study on BaxDelta2, covering the structure-function relationship, the clinical potential, and the human tissue expression profile.
Unlike Bax?, BaxDelta2 forms aggregates and triggers non-mitochondrial cell death through caspase 8. However, the functional domain(s) responsible for BaxDelta2 unique behavior were elusive. Here we show that disruption of helix alpha1 makes Baxalpha mimic BaxDelta2, but other alterations in the N-terminus have no significant impact. We found that the core region is key for aggregation, but is not sufficient to trigger cell death. The C-terminal helical conformation, not its primary sequence, appears to be critical for caspase 8 activation. As BaxDelta2 shares core and C-terminal with most Bax isoforms, our results indicate an intrinsic potential for aggregate-mediated caspase 8-dependent cell death in other Bax family members.
BaxDelta2 has been shown to sensitize cancer cells to chemotherapy, but it is a very unstable protein. Therefore, we screened a panel of proteasome inhibitors in colorectal cancer cells with different Bax statuses. We found that proteasome inhibitors can block BaxDelta2 degradation without affecting the levels of Baxalpha or Bcl-2. Among the inhibitors tested, bortezomib and carfilzomib were able to induce significantly higher cell death in BaxDelta2-positive cells than in cells with Baxalpha or no Bax. Furthermore, bortezomib-induced cell death in BaxDelta2-positive cells was predominantly dependent on the caspase 8/3 pathway. These results suggest that BaxDelta2 can selectively sensitize cancer cells to proteasome inhibitors.
As many cancers have microsatellite mutations, we screened BaxDelta2 protein expression in 1090 samples of tumor and healthy tissues from several organs. We found that BaxDelta2 is expressed in 1% to 5% of cells in most organs, predominantly in healthy tissues. Production of BaxDelta2 requires a guanine deletion in the microsatellite region, but the great majority of BaxDelta2-positive tissues contained no mutation at genomic or transcript levels. Therefore, we tested Programed Ribosomal Frameshift (PRF) as a possible BaxDelta2 expression mechanism, using a double tagged construct with no mutation. We found that, though rare, PRF can lead to expression of BaxDelta2.
In conclusion, BaxDelta2 can be expressed without a genetic mutation. In conclusion, BaxDelta2 is a unique isoform whose expression is the product of the extreme plasticity of the Bax gene and the biochemical circumstances in the cell. As an example of non-traditional expression, it opens the door to a whole new proteome expressed by alternative mechanisms both under physiological and pathological conditions.
Notlar:
School code: 0091
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(690796.1) | 690796-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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