Sedorovitz, Morgan
(2020)
Transcriptional Regulation of Angiotensinogen by Oncogenic K-Ras.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
As we age, our cells undergo irreversible growth arrest known as cellular senescence. Cells can undergo replicative senescence, which is caused by telomere shortening, or they can undergo stress-induced premature senescence (SIPS) which can be caused by oncogenic activation, DNA damage, cytotoxic drugs, and oxidative stress. Since senescent cells cannot replicate, cellular senescence is a powerful tumor suppressor mechanism. Lung cancer is the most common cancer worldwide and a continued public health issue. Despite public health efforts to reduce lung cancer cases by informing the public of the dangers of smoking, it remains a major public health concern.
Oncogenic K-Ras promotes senescence in normal cells but fuels transformation of cancer cells after the senescence barrier is bypassed. The mechanisms regulating this pleiotropic function of K-Ras remain to be fully established and bear high pathological significance. Angiotensinogen (AGT) is the precursor to Angiotensin II, a main regulator of systemic blood pressure. Our laboratory has novel findings showing that Ang II induces senescence in normal cells but boosts transformation in lung cancer cells. Here, we tested the hypothesis that oncogenic K-Ras activates the AGT gene promoter both in normal and lung cancer cells through different molecular mechanisms. We find that K-RasG12V activates the AGT promoter in normal cells through the transcription factor KLF6. We also show that AGT protein expression is elevated in non-small cell lung cancer cells expressing K-RasG12V and that the transcription factor HMGA1 activates the AGT promoter in these cells. STAT3 signaling is activated in lung cancer. We find that downregulation of HMGA1 inhibits STAT3 activation in lung cancer cells. Taken together, these results indicate that KLF6 and HMGA1 are key transcription factors through which oncogenic K-Ras activates the AGT/Ang II pathway in normal and lung cancer cells, respectively. Thus, KLF6 and HMGA1 represent therapeutic targets that can be exploited to develop novel anticancer interventions aimed at boosting oncogene-induced senescence in normal cells while inhibiting cell transformation of lung cancer cells.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
31 July 2020 |
| Date Type: |
Publication |
| Defense Date: |
17 April 2020 |
| Approval Date: |
31 July 2020 |
| Submission Date: |
30 March 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
45 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Angiotensinogen
Cellular senescence
Oncogene induced senescence |
| Date Deposited: |
31 Jul 2020 05:40 |
| Last Modified: |
01 May 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38442 |
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