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Mitochondrial Stress‐Induced Transcription Activation of Nuclear Genes Involves a Common Transcription Co‐Activator, hnRNPA2
Author(s) -
Guha Manti,
Amuthan Govindasamy,
Pan Hua,
Fang Ji Kang,
Avadhani Narayan
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a509-a
Subject(s) - transcription factor , microbiology and biotechnology , creb , biology , activator (genetics) , transcription (linguistics) , chemistry , gene , genetics , linguistics , philosophy
Partial depletion of mitochondrial DNA (mtDNA) in C2C12 myocytes initiates a mitochondrial retrograde signaling which alters expression of large number of genes including those involved in Ca 2+ storage/release (RyR1), glucose metabolism (Glut4, Hexokinase, IRS1), and oncogenesis (cathepsin L, IGF1R). In this study we have investigated the mechanism of mitochondrial stress‐induced upregulation of prototype genes, cathepsin‐L, RyR1 and Glut 4. Promoter constructs of all three genes yield 3–4 fold higher transcription activity in mtDNA depleted C2C12 cells. A common feature of mitochondrial stress‐responsive genes is the presence of binding sites for NFκB (cRel:p50), C/EBPδ, CREB, and NFAT at their 5′ proximal regions. Results of mutagenesis, co‐transfection and CHIP analyses show the need for atleast three factors for maximal stress‐responsive activation. Promoter pull down experiments (cathepsin L, RyR1) confirmed the association of these factors and also identified hnRNPA2 as a common stress‐activated protein that occupies the promoter sites. The binding of hnRNA2 to transcriptome requires the presence of at least three transcription factors and involves mostly protein‐protein interaction. Co‐immunoprecipitation shows physical interaction of hnRNPA2 with cRel:p50, C/EBPδ, CREB. Cotransfections show functional interaction with all four factors as indicated by cooperativity. Selective inhibition of IkBβ mediated activation of cRel:p50 or Ca 2+ chelators affecting hnRNPA2 recruitment abrogate stress mediated transcription activation and tumor progression. This study for the first time describes a mitochondrial stress induced transcription activation. (supported by NIH grant CA‐22762).