Eylem Seç
Activation of SAPKs, MAPKs and Downstream Targets by Hypoxia
Başlık:
Activation of SAPKs, MAPKs and Downstream Targets by Hypoxia
Yazar:
Conrad, P. William, author.
ISBN:
9780438034792
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (95 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: David Millhorn.
Özet:
Hypoxic/ischemic trauma is a primary factor in the pathology of various vascular, pulmonary, and cerebral disease states. Yet, very little is known about the signaling mechanisms by which cells respond to changes in O 2 levels. The effects of hypoxia on the stress- and mitogen-activated protein kinase (SAPK and MAPK) signaling pathways were studied in PC12 cells. Exposure to moderate hypoxia (5% O2) was found to progressively stimulate phosphorylation of the stress-activated protein kinase, p38alpha (3.1 fold), and a second isoform of this enzyme, p38gamma (5.9 fold). In contrast, hypoxia had no effect on enzyme activity of p38beta, p38beta 2, p38delta, or on JNK, another stress-activated protein kinase. Hypoxia also activated p42/p44 MAPK. Thus, hypoxia regulates specific members of the MAPK and SAPK families.
The SAPKs and MAPKs mediate their biological effects via the phosphorylation of downstream kinases, transcription factors, and proteins. Thus, we were interested in identifying targets of the p38 and MAPK pathways during hypoxia. Expression of the cyclin D1 gene has previously been shown to be negatively regulated by p38alpha (Lavoie et al., 1996). Hypoxia also dramatically down-regulated cyclin D1 immunoreactivity (~80% decreased from control levels). This effect was partially blocked by SB203580, an inhibitor of p38alpha, but not p38gamma. Over-expression of a kinase-inactive form of p38gamma was also able to partially reverse the effect of hypoxia on cyclin D1 levels, suggesting that the p38alpha and p38gamma isoforms converge to regulate cyclin D1 during hypoxia.
p42/p44 MAPK is known to phosphorylate a number of transcription factors. Endothelial PAS-domain protein 1 (EPAS1) is a transcription factor that rapidly accumulates upon exposing cells to hypoxia. We hypothesized that MAPK was involved in the regulation of EPAS1. Pre-treatment of PC12 cells with the MEK inhibitor, PD98059, completely blocked hypoxia-induced trans-activation of a hypoxia response element reporter gene (HRE-luc) by transfected EPAS1. We further show that pre-treatment with calmodulin antagonists nearly completely blocked both the hypoxia-induced phosphorylation of MAPK and the EPAS1 trans-activation of HRE-luc. These results demonstrate that the MAPK pathway is a critical mediator of EPAS1 activation and that activation of MAPK and EPAS1 occurs through a calmodulin-sensitive pathway.
Notlar:
School code: 0045
Konu Başlığı:
Tüzel Kişi Ek Girişi:
Mevcut:*
Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684168.1) | 684168-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
On Order
Liste seç
Bunu varsayılan liste yap.
Öğeler başarıyla eklendi
Öğeler eklenirken hata oldu. Lütfen tekrar deneyiniz.
:
Select An Item
Data usage warning: You will receive one text message for each title you selected.
Standard text messaging rates apply.