When hypoxia signalling meets the ubiquitin-proteasomal pathway, new targets for cancer therapy.
The ubiquitin-proteasomal pathway of degradation of proteins is activated or repressed in response to a number of environmental stresses and thereby plays an essential role in cell function and survival. Hypoxic stress, resulting from a decrease in the concentration of oxygen in tissues, is encountered in both physiological and pathological situations, in particular in cancer. The transcriptional complex hypoxia-inducible factor (HIF) is the key player in the signalling pathway that controls the hypoxic response of mammalian cells. Under hypoxic conditions it transactivates an impressive number of genes involved in a multitude of cellular functions. Tight regulation of this response in part involves the ubiquitin-proteasomal system where oxygen-dependent prolyl-4-hydroxylation of the alpha subunit of HIF triggers a cascade of events that leads to its degradation by the 26S proteasome. Inhibition of the proteasome in conjunction with topoisomerase inhibition has shown some promise in the treatment of experimental cancer. Such treatment may impact on the hypoxic adaptation of tumour cells.
Brahimi-Horn
Christiane
C
Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, 06189 Nice, France. brahimi@unice.fr
Pouysségur
Jacques
J
D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D009369:Neoplasms / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D025801:Ubiquitin / Q000187:drug effects / Q000378:metabolism*
D011480:Protease Inhibitors; D014157:Transcription Factors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex