Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''ATF4''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
This gene encodes a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (
CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the
AP-1 family of transcription factors, cAMP-response element binding proteins (
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
s) and CREB-like proteins. These transcription factors share a
leucine zipper
A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...
region that is involved in protein–protein interactions, located
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
to a stretch of basic amino acids that functions as a
DNA-binding domain
A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
. Two alternative transcripts encoding the same protein have been described. Two
pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication.
ATF4 transcription factor is also known to play role in
osteoblast
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
differentiation along with
RUNX2
Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...
and
osterix.
Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of
JNK
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and ar ...
. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.
IMPACT protein regulates ATF4 in C. elegans to promote lifespan.
Translation
The translation of ATF4 is dependent on
upstream open reading frames located in the
5'UTR.
The location of the second uORF, aptly named uORF2, overlaps with the ''ATF4'' open-reading frame. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ''ATF4'' ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the
40S
The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal pa ...
ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead ''ATF4'' is translated.
See also
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Activating transcription factor
References
Further reading
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External links
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PDBe-KBprovides an overview of all the structure information available in the PDB for Human Cyclic AMP-dependent transcription factor ATF-4
{{Regulome
, activates = Runx2, nrf1,Bip
, inhibits = ATF4, CHOP
, activated_by = not, PERK
, inhibited_by =
Transcription factors