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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''ATF4''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
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 (
CREBs) 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 to a stretch of basic amino acids that functions as a
DNA-binding domain. Two alternative transcripts encoding the same protein have been described. Two
pseudogene
Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...
s 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 combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
differentiation along with
RUNX2 and
osterix.
Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of
JNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.
IMPACT protein regulates ATF4 in C. elegans to promote lifespan.
ATF4 is also involved in the
cannabinoid
Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
Δ9-tetrahydrocannabinol–induced
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
in
cancer cells, by the proapoptotic role of the stress protein p8 via its upregulation of the
endoplasmic reticulum stress-related genes ATF4,
CHOP, and TRB3.
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 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
ATF4 (activating transcription factor 4)
{{Regulome
, activates = Runx2, nrf1, Bip
, inhibits = ATF4, CHOP
, activated_by = not, PERK
, inhibited_by =
Transcription factors