CREB3 subfamily transcription factors are not created equal: Recent insights from global analyses and animal models

Chi-Ping Chan,Kin-Hang Kok,Dong-Yan Jin

doi:10.1186/2045-3701-1-6

Abstract

The CREB3 subfamily of membrane-bound bZIP transcription factors has five members in mammals known as CREB3 and CREB3L1-L4. One current model suggests that CREB3 subfamily transcription factors are similar to ATF6 in regulated intramembrane proteolysis and transcriptional activation. Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR). Although the physiological inducers of their proteolytic activation remain to be identified, recent findings from microarray analyses, RNAi screens and gene knockouts not only demonstrated their critical roles in regulating development, metabolism, secretion, survival and tumorigenesis, but also revealed cell type-specific patterns in the activation of their target genes. Members of the CREB3 subfamily show differential activity despite their structural similarity. The spectrum of their biological function expands beyond ER stress and UPR. Further analyses are required to elucidate the mechanism of their proteolytic activation and the molecular basis of their target recognition.

Highlights

The CREB3 subfamily of bZIP transcription factors in mammals comprises CREB3, CREB3L1 (OASIS), CREB3L2 (BBF2H7), CREB3L3 (CREB-H) and CREB3L4 (AIbZIP) [1]
CREB3L2 was identified as part of a fusion oncoprotein named FUS-CREB3L2, which was generated by a chromosomal translocation in low grade fibromyxoid sarcoma (LGFMS) [4]
Similar to ATF6, they feature a transmembrane domain at the immediate C-terminal side of the bZIP region (Figure 1) [1,10]. They are type II membrane-associated proteins with the N-terminus facing the cytoplasm and the C-terminus penetrating through the endoplasmic reticulum (ER) membrane into the ER lumen [11,12]. Based on their structural similarity to ATF6, transcription factors of the CREB3 subfamily are thought to be activated through regulated intramembrane proteolysis (RIP) in response to ER stress [12]

Summary

Introduction

The CREB3 subfamily of bZIP transcription factors in mammals comprises CREB3 ( known as LZIP or Luman), CREB3L1 (OASIS), CREB3L2 (BBF2H7), CREB3L3 (CREB-H) and CREB3L4 (AIbZIP) [1]. Based on their structural similarity to ATF6, transcription factors of the CREB3 subfamily are thought to be activated through regulated intramembrane proteolysis (RIP) in response to ER stress [12]. These findings supported the model in which CREB3L2 activates the Sec23a-dependent pathway required for secretion of collagens and other extracellular matrix proteins during normal chondrogenesis [21].

Results

Conclusion