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Oxygen-dependent regulation of HIF-1alpha expression and function
- BokEngelska2009
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- Stockholm :Karolinska Institutet, Department of Cell and Molecular Biology,2009
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- LIBRIS-ID:oai:openarchive.ki.se:10616/38546
- ISBN:9789174096057
- 10616/38546hdl
- http://hdl.handle.net/10616/38546URI
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- Språk:engelska
- Sammanfattning på:engelska
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- Hypoxia is a state of reduced oxygen levels below normal values. It occurs in the pathophysiology of many diseases and plays important roles in mammalian physiology and development. The hypoxia-inducible factors (HIFs) are transcription factors that mediate adaptive cellular responses to hypoxia by activating the transcription of target genes. HIF is a heterodimer consisting of an oxygen-regulated alpha subunit and a constitutively expressed HIF-1beta (ARNT) subunit. Both HIF subunits belong to the bHLH/PAS domain-containing protein family. The bHLH and PAS domains mediate DNA binding and dimerization. HIF-alpha contains a unique oxygen-dependent degradation (ODD) domain and two transactivation domains (TADs: N-TAD and CTAD). The oxygen-dependent degradation of HIF-alpha is mediated by PHD-dependent hydroxylation, and subsequent pVHL-dependent ubiquitylation and proteasomal degradation. Under hypoxia, HIF-alpha is stabilized and accumulates in the nucleus where it dimerizes with ARNT and activates target gene expression by recruiting coactivators. FIH-1 inhibits the transcriptional activity of HIF-alpha by inhibiting the recruitments of coactivators such as CBP/p300 through the hydroxylation of Asparagine residue in CTAD. The aim of this study is to investigate in detail oxygen-dependent regulation of HIF-alpha degradation and function. In paper I, we identified residues that are critical for the degradation and transactivation functions of HIF-1alpha N-TAD. In paper II, we demonstrated that the expression of pVHL-interacting peptides activates endogenous HIF-1alpha function, providing a potential pro-angiogenic stimulus. The degradation of HIF-1alpha is regulated by subcellular compartmentalization in a cell-type-dependent manner. The compartment in which degradation of HIF-1alpha occurs dictates where the pVHL-interacting peptide must be located in order to efficiently increase HIF-1alpha function at normoxia. In paper III, we identified filamin A (FLNa) as a novel modulator of the HIF-1alpha pathway and presented a novel nuclear function of this actin-binding protein. Hypoxia enhances calpain-mediated cleavage of FLNa and the nuclear localization of the cleaved C-terminal fragment of FLNa. The C-terminal fragment of FLNa mediates the function of FLNa by facilitating the nuclear localization and enhancing the transcriptional activity of HIF-1alpha. FLNa promotes VEGF-A-mediated angiogenesis through activating HIF-1alpha-mediated hypoxic responses. In paper IV, we demonstrated how hypoxia controls the differentiation status of a cell and demonstrates a crosstalk between the HIF-1alpha and Notch signaling pathways. Hypoxia blocks differentiation in myoblasts, satellite cells and primary neural stem cells in a Notch-dependent manner. Hypoxia stabilizes the Notch intracellular domain, activates Notch-responsive promoters and increases expression of Notch-regulated downstream genes. The modulation of the Notch pathway by hypoxia is mediated by HIF-1alpha. HIF-1alpha interacts with Notch ICD, binds to Notch-responsive promoter, and a transcriptionally active form of HIF-alpha increases Notch signaling. The results from these studies contribute to a better understanding of the mechanism, which controls oxygen-dependent regulation and function of HIF-1alpha, and provide therapeutic implications by novel means to modulate the HIF-1alpha signaling pathway.
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- Karolinska Institutet
- Karolinska Institutet
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