Activated pp60c-Src leads to elevated hypoxia-inducible factor (HIF)-1alpha expression under normoxia.
Hypoxia-inducible factor (HIF)-1 is a master transcription factor, which up-regulates glycolysis, erythropoiesis, and angiogenesis under hypoxia. HIF-1alpha accumulates in normoxic tumor cells, leading to glycolysis under aerobic conditions. This phenomenon, known as the "Warburg effect," is caused by a yet unknown mechanism. Here we show that transformed cells that express constitutively active pp60(c-Src) (Src) express HIF-1alpha protein under normoxia, which results in the expression of multiple HIF-1alpha target genes. We show that this occurrence is due to an enhanced rate of HIF-1alpha protein synthesis and not due to reduced HIF-1alpha degradation. Furthermore, we show that the Src-induced increase in protein synthesis is due to the global increase in the rate of cap-dependent translation and does not involve inhibition of HIF-1alpha degradation.
Karni
Rotem
R
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Dor
Yuval
Y
Keshet
Eli
E
Meyuhas
Oded
O
Levitzki
Alexander
A
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006207:Half-Life; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D014176:Protein Biosynthesis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016392:Proto-Oncogene Proteins pp60(c-src)