title: Beclin-1-independent autophagy positively regulates internal ribosomal entry site-dependent translation of hypoxia-inducible factor 1α under nutrient deprivation.
abstract: Hypoxia has been shown to induce hypoxia-inducible factor-1alpha (HIF-1α) expression to support many cellular changes required for tumor growth and metastasis. In addition to hypoxia, nutrient deprivation is another stress condition widely existing in solid tumors due to the poor blood supply. Our data showed that nutrient deprivation induces a significant HIF-1α protein expression and potentiates the HIF-1α responses of hypoxia and CoCl2. This effect is not because of enhancement of HIF-1α stability or transcription. Rather we found it is through the cap-independent but internal ribosome entry site (IRES)-dependent translation. Notably inhibition of autophagy by si-ATG5, 3-methyladenine and chloroquine, but not si-Beclin-1, significantly reverses nutrient deprivation-induced HIF-1α responses. Furthermore, it is interesting to note the contribution of IRES activation for hypoxia-induced HIF-1α expression, however, different from nutrient starvation, si-Beclin 1 but not si-ATG5 can inhibit hypoxia-induced HIF-1α IRES activation and protein expression. Taken together, we for the first time highlight a link from alternative autophagy to cap-independent protein translation of HIF-1α under two unique stress conditions. We demonstrate Beclin 1-independent autophagy is involved to positively regulate nutrient deprivation induced-HIF-1α IRES activity and protein expression, while ATG5-independent autophagy is involved in the HIF-1 IRES activation caused by hypoxia.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ching-An
authors.initials: CA
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Duen-Yi
authors.initials: DY
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D015151:Immunoblotting; D008565:Membrane Proteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins