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DEC1 and DEC2 genes encode transcription factors which
belong to the Hairy/Enhancer of Split subfamily of basic helix-loop-helix (bHLH)
factors. The gene
expression of DEC2 is regulated in a cell type-specific manner, whereas that of
DEC1 is distributed ubiquitously in adult tissues, with the highest expression
in cartilage, spleen, lung and intestine. The encoded proteins of DEC1 and DEC2
play vital roles in many biological processes including development, cell
differentiation, cell growth, cell death, immune regulations, circadian
rhythms, and oncogenesis. Disorder of DEC1 and/or DEC2 in mammalian and the
corresponded diseases were discussed here.
Keywords:
DEC1/Stra13/SHARP-2; DEC2/mDEC2/SHARP-1; Circadian Rhythm; Hypoxia;
Abbreviations:
DEC: Differentiated Embryonic Chondrocyte, bHLH: Basic Helix-Loop-Helix, HIF:
Hypoxia Inducible Factor, HRE: Hypoxia Response Element
1. INTRODUCTION
Human DEC1 cDNA was cloned
from a human embryo chondrocytes cultured with dibutyryl cyclic AMP [1]. The mouse, rat form were named
as the stimulated with retinoic acid 13 (Stra13) [2] and the enhancer of split- and hairy-related
protein-2 (SHARP-2) [3], respectively. Human DEC1
consists of 412 amino acid residues, with molecular mass 45510 Da. There is a
bHLH domain ranged among 50-111 amino acids in the N-terminal region, an Orange
domain from 140-184 amino acids in the central region, as well as a
proline-rich domain span 310-385 amino acids in the C-terminal region. Region
1-139 is essential for interaction with ARNT/BMAL1, E-box binding and repressor
activity against the CLOCK-ARNT/BMAL1 heterodimer, while region 75-79 is
necessary for interaction with retinoid X receptor (RXR) α and repressor
activity against RXRα [4]. Fujimoto K et al. cloned human
DEC2 by performing 5’- and 3’-RACE (Rapid Amplification of cDNA Ends) with
human chondrocyte cDNA [5]. Human DEC2 protein contains 482
amino acids with a molecular weight of 50498 Da. The rat and mouse homologue
were named as the enhancer of split- and hairy-related protein-1 (SHARP-1), and
mDEC2 and mSHARP-1, respectively [3, 6, 7].
2. Expression of
DEC1 and DEC2
The expression of DEC1 and DEC2 is regulated by various extracellular
stimuli, such as growth factors [3, 8], hypoxia [9], hormones [10-12], and cytokines [13].
2.1 DNA/RNA
expression of DEC1 and DEC2
According
to the Entrez-Gene, DEC1 gene maps to NC_000003.12 in the region between
4979412 and 4985181 on the minus strand and spans across 5.7 kilo bases with 5
exons and 4 introns. DEC1 mRNA (NCBI Reference Sequence: NM_003670.2) has 3061
bps. On the other hand, DEC2 gene maps to NC_000012.12 in the region between 26120026
and 26125070 on the minus strand and spans across 5.0 kilo bases and consists
of 5 exons and 4 introns. DEC2 mRNA (NM_030762.2) has 3796 bps. Northern blot
and RT-PCR analysis showed that the mRNA expression of DEC2 was in a tissue- or
cell-type restricted manner. High expression is found in the heart, skeletal
muscle, and brain, while low expression is found in the lung, placenta,
pancreas [3, 5]. However, DEC1 mRNA ubiquitously distributed
in adult tissues [1, 3].
2.2 Protein
expression of DEC1 and DEC2
Protein sequence of DEC1 and DEC2 is not well conserved between mammals;
however, the bHLH motif in the N-terminal is highly conserved, that is, the
homology of DEC1 and DEC2 in bHLH motif is 97%. While the similarity in the
Orange domain is 52%. In addition, the overall homology between the two
proteins is 42%.
The bHLH domain, commonly found in many sequence specific DNA-binding
proteins, consists of a conserved core of approximately 50 amino acids in a
pattern of two amphipathic helices joined by a variable length linker region
that could form a loop with an extra basic region about 15 amino acid residues.
The HLH domain mediates the homo- or hetero-dimerization which is necessary for
DNA binding, and the basic region is required for DNA binding activity. DEC1
and DEC2 recognize and bind to a class B, also known as the canonical E-box
sequence, 5’-CACGTG-3’ with high affinity. It can also bind variations on the
sequence 5'-CANNTG-3' (where N is any nucleotide sequence), but not an N-box
with a sequence 5’-CACNAG-3’. The Orange domain present in both DEC1 and DEC2
makes them different from other bHLH family proteins. It is reported to be
involved in regulating cell differentiation, embryonic patterning, as well as
other biological processes including tumorigenesis and tumor progression [14, 15]. Few studies have discussed the
function of Alanine/Glycine-rich domain. However, several researchers
speculated that it is the Alanine/Glycine-rich domain that differentiates the
role of DEC2 from that of DEC1 in tumorigenesis progress such as regulating
apoptosis and epithelial-mesenchymal transitions [16, 17].
3. Functions of DEC1
and DEC2 and relations with disease
The expression of DEC1 and DEC2 is regulated by various extracellular
stimuli. The mRNA of DEC2 was induced by NGF (nerve growth factor) in PC12
cells [3]. And many kinds of cytokines can induced the protein and/or mRNA of DEC1
and DEC2, such as TNF-α [18] and IFN-β [13]. In addition, expression of DEC2 is
in response to the treatment with polyinosinic-polycytidylic acid (poly-IC), an
authentic double-stranded RNA in human mesangial cells [19]. Moreover, DEC1 and
DEC2 are reported to be regulated by some anti-cancer drugs, such as paclitaxel
and cisplatin, in a cell-specific type [20, 21]. Consequently, these
transcription factors play pivotal roles in multiple biological processes
including development, cell growth, cell death, oncogenesis, immune system,
circadian rhythm, and homeostasis.
3.1 Roles of DEC1
and DEC2 in developmental regulation
DEC1 is expressed in neural system, heart, skeletal muscles, thymus,
kidney, and the gastrointestinal tract of the developing mouse embryos. In
adult mouse embryos, it is detected in brain, liver, female genital tract,
lung, kidney, spleen and heart [2]. DEC1 may transcriptionally repress
mesodermal and endodermal differentiation and induce neuronal differentiation
in P19 cells [2].
In situ hybridization analysis revealed that DEC2 mRNA is expressed in
specific dorsal regions of the developing brain, heart, eye, the olfactory
system, limb buds, liver, prevertebrae of the developing mouse embryos [22]. In
adult mouse tissues, DEC2 is mainly found in skeletal muscle and brain [5].
Besides, DEC1 and DEC2 participate in mammary gland development in a mutually
exclusive manner, that is, DEC1 mRNA is strongly involved in the early stage of
involution whereas DEC2 mRNA appeared only during late stages of involution
[10].
3.2 Roles of DEC1
and DEC2 in cell differentiation and growth
Both DEC1 and DEC2 participate in the process of cell differentiation
and cell growth. The level of DEC1 mRNA is rapidly induced during the
differentiation of trophoblast giant cell [2, 23], neuron [2, 3], chondrocyte [1, 8] during mouse embryo development.
DEC1 mRNA is also increased at the early stage of 3T3-L1 and 3T3-F442A
preadipocytes when treated by adipogenic stimuli [12, 24]. However, the upregulated
expression of DEC1 related to the inhibition of preadipocytes differentiation
into adipocytes by transcriptionally repressed peroxisome
proliferator-activated receptor (PPAR) γ, which is one of the key regulators of
adipogenesis [25]. Additionally, DEC1 functioned as one of the
transcription factors and is involved in some aspects of the osteogenic differentiation
process of mesenchymal stem cells (MSC), although DEC1 alone cannot induce the
whole osteogenic differentiation program [26].
In vitro experiment indicated that co-expression
of DEC2 and MyoD blocked the differentiation of C2C12 myoblast cells and C3H10T1/2
into myotube cells [7, 27]. DEC2 interrupted the
MyoD-dependent transcription stimulation of differentiation-specific marker
genes such as myogenin, MEF2C, and myosin heavy chain by protein-protein interaction
with MyoD [27]. Small ubiquitin-like modifier (SUMO) modification of the
transcription factor DEC2 is required for its full transcriptional repression
activity and function as an inhibitor of skeletal muscle differentiation. DEC2
is modified by sumoylation at two conserved lysine residues 240 and 255.
Mutation of these SUMO acceptor sites in DEC2 attenuates its ability to act as
a transcriptional repressor and inhibit myogenic differentiation [28].
3.3 Roles of DEC1
and DEC2 in circadian rhythms
Circadian rhythms, about 24 h-cycle rhythms exist in living systems,
are generated by a set of genes forming a transcriptional auto-regulatory
feedback loop. In mammals, Clock, Bmal1,
Per1, Per2, Cry1, Cry2 genes constitute this feedback loop. The
suprachiasmatic nucleus (SCN) of the hypothalamus is identified as the dominant
circadian pacemaker driving rhythms in activity and rest, feeding, body
temperature and hormones of mammals [29]. The existence of peripheral clocks has been
reported in the liver, kidney, lung and other organs [30-32]. Dec1 and Dec2, described
by Honma S, et al. as members of the
fifth clock-gene family, repress
Clock/Bmal1-induced transactivation of the mouse Per 1 promoter through protein-protein
interaction with Bmal1 [33]. They expressed higher during the day and
this circadian pattern cannot be changed under conditions of constant darkness.
DEC1 shows robust circadian expression in the SCN as well as in various
peripheral tissues [33-38]. However, the expression pattern
of DEC1 and DEC2 in peripheral tissues differs from that of SCN [38]. In the
SCN, the expression of both DEC1 and DEC2 mRNA exhibited a peak in the
subjective day [33], while in the peripheral tissues, the higher
expression is appeared during the subjective night [38].
3.4 Roles of DEC1
and DEC2 in hypoxia treatment
The expression of DEC1 and DEC2 mRNAs is upregulated by hypoxia [9, 25, 39-41]. Functional hypoxia response
elements (HRE) are identified in the transcriptional regulatory region of both
DEC1 and DEC2. It exists at the nucleotide sequences between -462 and -446 (5’-GGCCAGACGTGCCTGGA-3’)
of human DEC1 gene, and localizes
between -311 and -295 (5’-TTCCGCACGTGAGCTGG-3’) of human DEC2 gene [9]. Hypoxia inducible factor (HIF)-1
binds to the HRE element and stimulates the transcription of both DEC1 and DEC2 genes, consequently suppressing the expression of their target
genes under hypoxic conditions, because they usually work as transcriptional
suppressors in vitro [6, 42-44]. In addition, DEC2 gene
contributes to the hypoxic adaptation among long-term high-altitude residents
such as Ethiopian, Andean, and Tibetan populations living at high altitude
through affecting target genes from the HIF-1α-DEC2-VEGF pathway [45]. On the other hand, hypoxia-mediated
changes in circadian rhythms have been suggested to be a key driver of the
sleep fragmentation and poor sleep quality seen in lowlanders at high altitude.
DEC2 may provide insights into the crosstalk between hypoxia and circadian
clock [45]. Pathologically, hypoxic
conditions are often present in the inner of most solid tumors. It has been
reported that lower DEC2 mRNA level were detected in colon carcinoma tissue
than in the adjacent normal tissue which probably caused by the strong
expression of DEC1 in the carcinoma cells [46]. Since the expression of DEC2 was
inhibited by DEC1 through binding to the E-box which located in its promoter
region [46].
3.5 Function of DEC1
and DEC2 in cancer
Abnormal expression of DEC1 and DEC2 is found to be related to various kinds of malignant tumors generally
because their roles in cell proliferation, apoptosis, hypoxia responses. Montagner
et al. showed that DEC2 is a crucial
regulator of the invasive and metastatic phenotype in triple- negative breast
cancer (TNBC), one of the most aggressive types of breast cancer [47]. DEC2 is
upregulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness
through inhibition of HIF1α and HIF2α as well as their target genes. DEC2
opposes HIF-dependent TNBC cell migration in
vitro, and invasive or metastatic behaviors in vivo. Mechanistically, DEC2 binds to HIFs and promotes HIF
proteasomal degradation by serving as the HIF-presenting factor to the
proteasome. This process is independent of the VHL (Von Hippel-Lindau) tumor
suppressor, hypoxia, and the ubiquitination machinery. DEC2 therefore
determines the intrinsic instability of HIF proteins to act in parallel to, and
cooperate with, oxygen levels.
3.6 Mutation of DEC2 gene results in short sleep
In a mother and daughter with the short sleep phenotype, He et al. identified a heterozygous C-to-G
transversion in the DEC2 gene, resulting in a pro384-to-arg (P384R)
substitution in a highly conserved region within a proline-rich domain close to
the C terminus [48]. Both individuals showed normal
sleep-onset times, but much earlier sleep-offset time (time of awakening)
compared to family members and age-matched controls. The short sleeper phenotype
or trait is not considered a sleep disorder. Individuals with this trait
require less sleep in any 24-hour period than is typical for their age group.
In vitro functional expression studies showed that the P384R protein attenuated
Dec2 repressive activity of Clock /Bmal1-induced transactivation. Transgenic
mice carrying the heterozygous P384R mutation showed increased vigilance time
and less sleep time than control mice.
4. CONCLUSIONS
We reviewed our current understanding of the bHLH transcription factors
DEC1 and DEC2, including structures, functions, as well as their roles in
various diseases. Recently reports show that not only normal cells but also
cancer cells own their rhythms in gene expression. This phenomenon has been
used in cancer therapy known as chronotherapy. The multiple roles of DEC1 and
DEC2 in development, differentiation, and pathology as well as their functions
in circadian rhythm reveal the value of further understanding of their
functions.
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