Hypoxia-mediated control of HIF/ARNT machinery in epidermal keratinocytes

Autor: J. Keith Vass, L. Weir, A. Panteleyev, Irene M. Leigh, Douglas Robertson
Rok vydání: 2011
Předmět:
Keratinocytes
Vascular Endothelial Growth Factor A
Splicing
HIF3a
Mice
0302 clinical medicine
Gene expression
Basic Helix-Loop-Helix Transcription Factors
Hypoxia
Oligonucleotide Array Sequence Analysis
0303 health sciences
Reverse Transcriptase Polymerase Chain Reaction
Cell biology
ARNT
HIF3A
medicine.anatomical_structure
030220 oncology & carcinogenesis
medicine.symptom
Keratinocyte
Signal Transduction
medicine.medical_specialty
Aryl hydrocarbon receptor nuclear translocator
Blotting
Western
Enzyme-Linked Immunosorbent Assay
HIF1a
Biology
Protein degradation
03 medical and health sciences
Downregulation and upregulation
Internal medicine
medicine
Animals
Humans
RNA
Messenger
Molecular Biology
030304 developmental biology
Gene Expression Profiling
Aryl Hydrocarbon Receptor Nuclear Translocator
Cell Biology
Hypoxia (medical)
Mice
Inbred C57BL
Repressor Proteins
Alternative Splicing
HIF1A
Endocrinology
Animals
Newborn
Epidermis
Apoptosis Regulatory Proteins
Biomarkers
Zdroj: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1813(1):60-72
ISSN: 0167-4889
DOI: 10.1016/j.bbamcr.2010.11.014
Popis: Transcriptional activity of hypoxia-induced factor 1 (HIF1) – a heterodimer of HIF1α and ARNT (HIF1β) – is essential for cellular adaptation to environmental stress and plays an important role in skin development, wound healing, tumorigenesis and barrier function. Using primary mouse and human epidermal keratinocytes at ambient or hypoxic (1% O2) conditions we studied effects of hypoxia upon HIF protein expression. Significant nuclear levels of ARNT and HIF1α along with high HIF1 activity in normoxic keratinocytes suggest an as yet uncharacterised oxygen-independent role for HIF pathway in the epidermis. Acute hypoxia results in an instant but transient increase of HIF1α protein accompanied by a gradual decrease in its mRNA, while ARNT expression remains unchanged. In prolonged (chronic) hypoxia both HIF1α and Arnt are downregulated along with decline of HIF1 activity. However, expression of classical HIF1 targets such as Selenbp1 and Vegfa remains high. Thus, keratinocytes respond to acute hypoxia with immediate block of HIF1α protein degradation and concomitant increase of HIF activity, while under chronic hypoxia pro-angiogenic signalling is maintained through HIF1-independent pathway(s). Decline of HIF1α during chronic exposure is controlled at both mRNA and protein levels, while Arnt is downregulated post-translationally. Distinct transcription levels of Hif1α and Hif3α splice variants under normoxia and their differential response to hypoxia suggest functional diversity of Hif-α isoforms and highlight the complexity of HIF machinery control in epidermal keratinocytes.
Databáze: OpenAIRE
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