Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities
Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically in humans for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism is that it prevents proteasomal degradation of pro-apoptotic proteins, leading to enhance apoptosis. Although the alp...
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| Format: | Thesis |
| Language: | English |
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2013
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| Online Access: | http://psasir.upm.edu.my/id/eprint/48690/1/FBSB%202013%2039R.pdf |
| _version_ | 1796975045792235520 |
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| author | Abd Aziz, Noraini |
| author_facet | Abd Aziz, Noraini |
| author_sort | Abd Aziz, Noraini |
| collection | UPM |
| description | Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically in humans for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed
mechanism is that it prevents proteasomal degradation of pro-apoptotic proteins, leading to enhance apoptosis. Although the alpha subunit of hypoxia inducible factor 1 (HIF-1) is not degraded, the heterodimeric HIF-1 fails to transactivate target genes. HIF-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for survival of hypoxic tumor cells. Most reports have focused on the effects of bortezomib on HIF-1 but not HIF-2 transcriptional activities. In the present study, the effect of bortezomib on HIF-2 activity in cells with different levels of expression of the HIF-1α and HIF-2α
subunits, was investigated. Results showed that bortezomib treatment suppressed the transcription and expression of CA9, a HIF-1-specific target gene, but had minimal
effects on EPO and GLUT-1, which are the target genes of both HIF-1 and HIF-2. A similar dichotomy of responses was also seen with exogenously-introduced hypoxia response elements of CA9 and EPO. These data led to a conclusion that bortezomib attenuates the transcriptional activity of only HIF-1 but not HIF-2. This novel finding on the lack of inhibitory effect of bortezomib on HIF-2 transcriptional activity will be important in the improvement of design and treatment modalities to enhance the efficacy of this and other proteasomal inhibitor drugs. |
| first_indexed | 2024-03-06T09:05:48Z |
| format | Thesis |
| id | upm.eprints-48690 |
| institution | Universiti Putra Malaysia |
| language | English |
| last_indexed | 2024-03-06T09:05:48Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | upm.eprints-486902016-10-14T08:08:09Z http://psasir.upm.edu.my/id/eprint/48690/ Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities Abd Aziz, Noraini Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically in humans for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism is that it prevents proteasomal degradation of pro-apoptotic proteins, leading to enhance apoptosis. Although the alpha subunit of hypoxia inducible factor 1 (HIF-1) is not degraded, the heterodimeric HIF-1 fails to transactivate target genes. HIF-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for survival of hypoxic tumor cells. Most reports have focused on the effects of bortezomib on HIF-1 but not HIF-2 transcriptional activities. In the present study, the effect of bortezomib on HIF-2 activity in cells with different levels of expression of the HIF-1α and HIF-2α subunits, was investigated. Results showed that bortezomib treatment suppressed the transcription and expression of CA9, a HIF-1-specific target gene, but had minimal effects on EPO and GLUT-1, which are the target genes of both HIF-1 and HIF-2. A similar dichotomy of responses was also seen with exogenously-introduced hypoxia response elements of CA9 and EPO. These data led to a conclusion that bortezomib attenuates the transcriptional activity of only HIF-1 but not HIF-2. This novel finding on the lack of inhibitory effect of bortezomib on HIF-2 transcriptional activity will be important in the improvement of design and treatment modalities to enhance the efficacy of this and other proteasomal inhibitor drugs. 2013-11 Thesis NonPeerReviewed application/pdf en http://psasir.upm.edu.my/id/eprint/48690/1/FBSB%202013%2039R.pdf Abd Aziz, Noraini (2013) Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities. Masters thesis, Universiti Putra Malaysia. Protease inhibitors - Therapeutic use Cancer - Chemotherapy |
| spellingShingle | Protease inhibitors - Therapeutic use Cancer - Chemotherapy Abd Aziz, Noraini Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities |
| title | Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities |
| title_full | Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities |
| title_fullStr | Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities |
| title_full_unstemmed | Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities |
| title_short | Effects of bortezomib on HIF-1 and HIF-2 transcriptional activities |
| title_sort | effects of bortezomib on hif 1 and hif 2 transcriptional activities |
| topic | Protease inhibitors - Therapeutic use Cancer - Chemotherapy |
| url | http://psasir.upm.edu.my/id/eprint/48690/1/FBSB%202013%2039R.pdf |
| work_keys_str_mv | AT abdaziznoraini effectsofbortezomibonhif1andhif2transcriptionalactivities |