Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN).
We describe a novel basic leucine zipper containing type I IFN-inducible early response gene SARI (Suppressor of AP-1, Regulated by IFN). Steady-state SARI mRNA expression was detected in multiple lineage-specific normal cells, but not in their transformed/tumorigenic counterparts. In normal and cancer cells, SARI expression was induced 2 h after fibroblast IFN (IFN-beta) treatment with 1 U/ml of IFN-beta. Antisense inhibition of SARI protected HeLa cells from IFN-beta-mediated growth inhibition. As a corollary, overexpression of SARI inhibited growth and induced apoptosis in cancer cells, but not in normal cells. SARI interacted with c-Jun via its leucine zipper, resulting in inhibition of DNA binding of activator protein (AP-1) complex and consequently AP-1-dependent gene expression. Transformed cells relying on AP-1 activity for proliferative advantage demonstrated increased susceptibility to SARI-mediated growth inhibition. These findings uncover a novel mode of IFN-induced anti-tumor growth suppression and suggest potential gene therapy applications for SARI.
Su
Zao-zhong
ZZ
Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Lee
Seok-Geun
SG
Emdad
Luni
L
Lebdeva
Irina V
IV
Gupta
Pankaj
P
Valerie
Kristoffer
K
Sarkar
Devanand
D
Fisher
Paul B
PB
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D016350:Leucine Zippers / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*
D050976:Basic-Leucine Zipper Transcription Factors; C569485:Batf2 protein, human; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D016899:Interferon-beta