HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature
- Mattison, Stacey A, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Mattison, Stacey A , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66278 , vital:28928 , https://doi.org/10.1007/s12192-016-0755-8
- Description: publisher version , The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation.
- Full Text: false
- Date Issued: 2018
- Authors: Mattison, Stacey A , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66278 , vital:28928 , https://doi.org/10.1007/s12192-016-0755-8
- Description: publisher version , The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation.
- Full Text: false
- Date Issued: 2018
Environmental and social recovery asymmetries to large-scale disturbances in small island communities
- Aswani, Shankar, Van Putten, Ingrid, Miñarro, Sara
- Authors: Aswani, Shankar , Van Putten, Ingrid , Miñarro, Sara
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/67325 , vital:29073 , https://doi.org/10.1007/s11069-016-2685-2
- Description: publisher version , People’s livelihoods in tropical small-island developing states are greatly dependent on marine ecosystem services. Yet services such as fisheries and coastal buffering are being degraded at an alarming rate, thus making people increasing vulnerable to protracted and sudden environmental changes. In the context of the occurrences of extreme events such as earthquakes and tsunamis, it is vital to uncover the processes that make people in these island states resilient, or not, to environmental disruptions. This paper compares people’s perceptions of social and environmental impacts after an extreme event in the Western Solomon Islands (11 different villages on 8 different islands) to better understand how knowledge systems influence the coupling of human and natural systems. We examine the factors that contributed to perceptions of respective recovery in the environmental versus the social domains across communities with different traditional governance and modernization characteristics in a tsunami impact gradient. First, we separately assessed, at the community and individual level, the potential determinants of perceived recovery in the environmental and social domains. At the community level, the average values of the perceived environmental and social recovery were calculated for each community (1 year after the tsunami), and at the individual level, normally distributed environmental and social recovery variables (based on the difference in perceptions immediately and 1 year after the tsunami) were used as dependent variables in two General Linear Models. Results suggest that environmental and social resilience are not always coupled correspondingly and, less unexpectedly, that asymmetries during recovery can occur as a result of the underlying social and ecological context and existing adaptive capacity. More generally, the study shows how by evaluating post-disturbance perceptional data in tsunami-affected communities, we can better understand how subjective perceptions of change can affect the (de)-coupling of human and natural systems.
- Full Text: false
- Date Issued: 2017
- Authors: Aswani, Shankar , Van Putten, Ingrid , Miñarro, Sara
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/67325 , vital:29073 , https://doi.org/10.1007/s11069-016-2685-2
- Description: publisher version , People’s livelihoods in tropical small-island developing states are greatly dependent on marine ecosystem services. Yet services such as fisheries and coastal buffering are being degraded at an alarming rate, thus making people increasing vulnerable to protracted and sudden environmental changes. In the context of the occurrences of extreme events such as earthquakes and tsunamis, it is vital to uncover the processes that make people in these island states resilient, or not, to environmental disruptions. This paper compares people’s perceptions of social and environmental impacts after an extreme event in the Western Solomon Islands (11 different villages on 8 different islands) to better understand how knowledge systems influence the coupling of human and natural systems. We examine the factors that contributed to perceptions of respective recovery in the environmental versus the social domains across communities with different traditional governance and modernization characteristics in a tsunami impact gradient. First, we separately assessed, at the community and individual level, the potential determinants of perceived recovery in the environmental and social domains. At the community level, the average values of the perceived environmental and social recovery were calculated for each community (1 year after the tsunami), and at the individual level, normally distributed environmental and social recovery variables (based on the difference in perceptions immediately and 1 year after the tsunami) were used as dependent variables in two General Linear Models. Results suggest that environmental and social resilience are not always coupled correspondingly and, less unexpectedly, that asymmetries during recovery can occur as a result of the underlying social and ecological context and existing adaptive capacity. More generally, the study shows how by evaluating post-disturbance perceptional data in tsunami-affected communities, we can better understand how subjective perceptions of change can affect the (de)-coupling of human and natural systems.
- Full Text: false
- Date Issued: 2017
The influence of dose on the kinetic parameters and dosimetric features of the main thermoluminescence glow peak in α-Al2O3: C, Mg
- Kalita, Jitumani M, Chithambo, Makaiko L
- Authors: Kalita, Jitumani M , Chithambo, Makaiko L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/119834 , vital:34787 , https://doi.org/10.1016/j.nimb.2016.12.027
- Description: The influence of dose (0.1–100 Gy) on the kinetic parameters and the dosimetric features of the main glow peak of α-Al2O3:C,Mg have been investigated. Thermoluminescence (TL) measured at 1 °C/s shows a very high intensity glow peak at 161 °C and six secondary peaks at 42, 72, 193, 279, 330, 370 °C respectively. Analysis shows that the main peak follows first order kinetics irrespective of the irradiation dose. The activation energy is found to be consistent at 1.37 eV and the frequency factor is of the order of 1014 s−1 for any dose between 0.1 and 100 Gy. Further, the analysis for thermal quenching of the main peak of 0.1 Gy irradiated sample shows that the activation energy for thermal quenching is (0.94 ± 0.04) eV.
- Full Text: false
- Date Issued: 2017
- Authors: Kalita, Jitumani M , Chithambo, Makaiko L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/119834 , vital:34787 , https://doi.org/10.1016/j.nimb.2016.12.027
- Description: The influence of dose (0.1–100 Gy) on the kinetic parameters and the dosimetric features of the main glow peak of α-Al2O3:C,Mg have been investigated. Thermoluminescence (TL) measured at 1 °C/s shows a very high intensity glow peak at 161 °C and six secondary peaks at 42, 72, 193, 279, 330, 370 °C respectively. Analysis shows that the main peak follows first order kinetics irrespective of the irradiation dose. The activation energy is found to be consistent at 1.37 eV and the frequency factor is of the order of 1014 s−1 for any dose between 0.1 and 100 Gy. Further, the analysis for thermal quenching of the main peak of 0.1 Gy irradiated sample shows that the activation energy for thermal quenching is (0.94 ± 0.04) eV.
- Full Text: false
- Date Issued: 2017
Unexpected transformations of 3-(bromoacetyl)coumarin provides new evidence for the mechanism of thiol mediated dehalogenation of α-halocarbonyls
- Magwenzi, Faith N, Khanye, Setshaba D, Veale, Clinton G L
- Authors: Magwenzi, Faith N , Khanye, Setshaba D , Veale, Clinton G L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66200 , vital:28916 , https://doi.org/10.1016/j.tetlet.2017.01.082
- Description: publisher version , The mechanism for the thiol mediated dehalogenation of α-halogenated carbonyls has remained an unresolved problem, despite its ongoing application in synthetic organic chemistry. Nakamura and co-workers first proposed that net dehalogenation occurs via sequential nucleophilic substitutions, while Israel and co-workers concluded that the rate at which dehalogenation occurred suggested that dehalogenation proceeds in a single concerted step. In this study, we investigated the debromination and nucleophilic substitution of 3-(bromoacetyl)coumarin with a variety of thiophenols, whose electron donating or withdrawing natures resulted in large variations in the degree of nucleophilic substitution and dehalogenation products, respectively. Results from these experiments, in addition to an unexpected formation of thioether containing dibenzo[b,d]pyran-6-ones from a Robinson annulation, has provided new evidence for this disputed mechanism.
- Full Text: false
- Date Issued: 2017
- Authors: Magwenzi, Faith N , Khanye, Setshaba D , Veale, Clinton G L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66200 , vital:28916 , https://doi.org/10.1016/j.tetlet.2017.01.082
- Description: publisher version , The mechanism for the thiol mediated dehalogenation of α-halogenated carbonyls has remained an unresolved problem, despite its ongoing application in synthetic organic chemistry. Nakamura and co-workers first proposed that net dehalogenation occurs via sequential nucleophilic substitutions, while Israel and co-workers concluded that the rate at which dehalogenation occurred suggested that dehalogenation proceeds in a single concerted step. In this study, we investigated the debromination and nucleophilic substitution of 3-(bromoacetyl)coumarin with a variety of thiophenols, whose electron donating or withdrawing natures resulted in large variations in the degree of nucleophilic substitution and dehalogenation products, respectively. Results from these experiments, in addition to an unexpected formation of thioether containing dibenzo[b,d]pyran-6-ones from a Robinson annulation, has provided new evidence for this disputed mechanism.
- Full Text: false
- Date Issued: 2017
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