Amino acid deprivation induces CREBZF/Zhangfei expression via an AARE-like element in the promoter

Abstract

CREBZF (also called ZF or Zhangfei) is a basic region–leucine zipper transcription factor that has been implicated in the herpesvirus infection cycle and related cellular processes. Since ATF4 is known to play a key role in cellular responses to various ER stresses as well as amino acid deprivation, we sought to examine the potential involvement of CREBZF in the amino acid response (AAR). We found that the CREBZF protein was induced by amino acid deprivation in the canine MDCK cells. We subsequently cloned a canine CREBZF promoter region (−1767 bp to +1 bp) that responds to amino acid limitation. Using deletion mapping and site-directed mutagenesis, we identified a 9-bp sequence 5′-ATTCACTCA-3′ in the promoter (−1227 to −1219), deletion of which resulted in a complete loss of inducibility by amino acid deprivation. This sequence is similar to the known amino acid response elements (AAREs) found in other AAR-inducible genes, such as CHOP (C/EBP homologous protein, also known as GADD153). These results suggest that CREBZF may be an amino acid stress sensor. Considering the AARE-like sequence found in CREBZF and other similarities between CREBZF and CHOP, we postulate that CREBZF and CHOP may be two sensors that regulate different yet related signaling pathways governing the AAR.