Elsevier

Gene

Volume 273, Issue 1, 25 July 2001, Pages 1-11
Gene

Review
The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis

https://doi.org/10.1016/S0378-1119(01)00551-0Get rights and content

Abstract

The mammalian ATF/CREB family of transcription factors represents a large group of basic region-leucine zipper (bZip) proteins which was originally defined in the late 1980s by their ability to bind to the consensus ATF/CRE site β€˜TGACGTCA’. Over the past decade, cDNA clones encoding identical or homologous proteins have been isolated by different laboratories and given different names. These proteins can be grouped into subgroups according to their amino acid similarity. In this review, we will briefly describe the classification of these proteins with a historical perspective of their nomenclature. We will then review three members of the ATF/CREB family of proteins: ATF3, ATF4 and ATF6. We will address four issues for each protein: (a) homologous proteins and alternative names, (b) dimer formation with other bZip proteins, (c) transcriptional activity, and (d) potential physiological functions. Although the name Activating Transcription Factor (ATF) implies that they are transcriptional activators, some of these proteins are transcriptional repressors. ATF3 homodimer is a transcriptional repressor and ATF4 has been reported to be either an activator or a repressor. We will review the reports on the transcriptional activities of ATF4, and propose potential explanations for the discrepancy. Although the physiological functions of these proteins are not well understood, some clues can be gained from studies with different approaches. When the data are available, we will address the following questions. (a) How is the expression (at the mRNA level or protein level) regulated? (b) How are the transcriptional activities regulated? (c) What are the interacting proteins (other than bZip partners)? (d) What are the consequences of ectopically expressing the gene (gain-of-function) or deleting the gene (loss-of-function)? Although answers to these questions are far from being complete, together they provide clues to the functions of these ATF proteins. Despite the diversity in the potential functions of these proteins, one common theme is their involvement in cellular responses to extracellular signals, indicating a role for these ATF proteins in homeostasis.

Section snippets

Introduction – a historical perspective and nomenclature

Activating Transcription Factor (ATF) was first named in 1987 to refer to proteins that bind to the adenovirus early promoters E2, E3 and E4 at sites with a common core sequence β€˜CGTCA’ (Lee et al., 1987). cAMP responsive element binding protein (CREB) was named in 1987 to refer to proteins that bind to the cAMP responsive element (CRE) on the somatostatin promoter (Montminy and Bilezsikjian, 1987). The consensus binding site for ATF was later defined as TGACGT(C/A)(G/A) (Lin and Green, 1988),

ATF3

ATF3 was originally isolated from a library derived from HeLa cells treated with tetradecanoylphorbol acetate (TPA) (Hai et al., 1989). Previously, we reviewed ATF3 and its potential roles in stress responses (Hai et al., 1999). Due to the space limit, we will briefly summarize the last review and discuss a few new findings since the last review.

Nomenclature, homologous proteins, and dimer formation of ATF4

A partial cDNA encoding the human ATF4 was isolated on the basis of its ability to bind to the consensus ATF/CRE site (Hai et al., 1989). Subsequently, full-length cDNA clones encoding identical or homologous proteins were isolated by a variety of methods. These include the human clones TAXCREB 67 (Tsujimoto et al., 1991) and CREB-2 (Karpinski et al., 1992), and the mouse clones mATF4 (Mielnicki and Pruitt, 1991, mapped to mouse chromosome 15, see Mielnicki et al., 1993), mTR67 (Chevray and

Nomenclature, homologous proteins, and dimer formation of ATF6

A partial cDNA encoding the human ATF6 was isolated on the basis of its ability to bind to the consensus ATF/CRE site (Hai et al., 1989). A human clone with significant similarity to ATF6 was isolated in an attempt to identify genes located in the HLA complex (Min et al., 1995). It was originally named CREB-related protein (CRB-RP), because it shares a small degree of homology to CREB: at the Nβ€² terminal region over a stretch of about 300 residues (from 83 to 375), it is 23% identical to CREB.

Conclusions and future perspectives

In conclusion, all three ATF proteins reviewed above (ATF3, ATF4 and ATF6) are modulated by extracellular signals (at the level of their expression or activity). These observations indicate that one common role for the ATF/CREB family of proteins is their involvement in homeostasis. Consistent with this notion, the CREB/CREM and CRE-BP1 (ATF2) subfamilies of proteins are also modulated by extracellular signals. CREB is expressed in most cell types, but the protein is phosphorylated after

Acknowledgements

This study was supported by NIEHS08690, Central Ohio Cancer Research, the Central Ohio Diabetes Association, and the American Diabetes Association (to T.H.).

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