HMGA2
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High-mobility group AT-hook 2, also known as HMGA2, 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 ''HMGA2''
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 protein that belongs to the non-
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
chromosomal
high-mobility group High-Mobility Group or HMG is a group of chromosomal proteins that are involved in the regulation of DNA-dependent processes such as transcription, replication, recombination, and DNA repair. History and name HMG proteins were originally isolate ...
(HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhanceosome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with
lipoma A lipoma is a benign tumor made of adipose tissue, fat tissue. They are generally soft to the touch, movable, and painless. They usually occur just under the skin, but occasionally may be deeper. Most are less than in size. Common locations inc ...
s suggests a role in adipogenesis and
mesenchymal Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood, or bone. The interactions between mesenchyme and epithelium help to form nearly ever ...
differentiation. A gene knock-out study of the mouse counterpart demonstrated that this gene is involved in diet-induced
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The expression of HMGA2 in adult tissues is commonly associated with both malignant and benign tumor formation, as well as certain characteristic cancer-promoting mutations. Homologous proteins with highly conserved sequences are found in other mammalian species, including lab mice (''
Mus musculus The house mouse (''Mus musculus'') is a small mammal of the rodent family Muridae, characteristically having a pointed snout, large rounded ears, and a long and almost hairless tail. It is one of the most abundant species of the genus ''Mus (genu ...
''). HMGA2 contains three basic
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 ...
s ( AT-hooks) that cause the protein to bind to
adenine Adenine (, ) (nucleoside#List of nucleosides and corresponding nucleobases, symbol A or Ade) is a purine nucleotide base that is found in DNA, RNA, and Adenosine triphosphate, ATP. Usually a white crystalline subtance. The shape of adenine is ...
-
thymine Thymine () (symbol T or Thy) is one of the four nucleotide bases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine ...
(AT)-rich regions of nuclear DNA. HMGA2 does not directly promote or inhibit the transcription of any genes, but alters the structure of DNA and promotes the assembly of protein complexes that do regulate the transcription of genes. With few exceptions, HMGA2 is expressed in humans only during early development, and is reduced to undetectable or nearly undetectable levels of transcription in adult tissues. The
microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
let-7 is largely responsible for this time-dependent regulation of HMGA2. The apparent function of HMGA2 in proliferation and differentiation of cells during development is supported by the observation that mice with mutant HMGA2 genes are unusually small (the pygmy or mini-mouse phenotype), and
genome-wide association studies In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWA studies typically focus on assoc ...
linking ''HMGA2''-associated
SNPs In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
to variation in human height.


Regulation by let-7

Let-7 inhibits production of specific proteins by complementary binding to their
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
transcripts. The HMGA2 mature mRNA transcript contains seven regions complementary or nearly complementary to let-7 in its 3' untranslated region (UTR). Let-7 expression is very low during early human development, which coincides with the greatest transcription of HMGA2. The time-dependent drop in HMGA2 expression is caused by a rise in let-7 expression.


Clinical significance


Relationship with cancer

Heightened expression of HMGA2 is found in a variety of human cancers, but the precise mechanism by which HMGA2 contributes to the formation of cancer is unknown. The same mutations that lead to
pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...
for the patient, but also with sensitization of the cancer cells to certain forms of cancer therapy. To be specific, HMGA2-high cancers display an abnormally strong response to double strand breaks in DNA caused by
radiation therapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a therapy, treatment using ionizing radiation, generally provided as part of treatment of cancer, cancer therapy to either kill or control the growth of malignancy, malignant cell (biology), ...
and some forms of
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
. Artificial addition of HMGA2 to some forms of cancer unresponsive to DNA damage cause them to respond to the treatment instead, although the mechanism by which this phenomenon occurs is also not understood. However, the expression of HMGA2 is also associated with increased rates of
metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
in
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
, and both metastasis and recurrence of
squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
. These properties are responsible for patients' poor prognoses. As with HMGA2's effects on the response to radiation and chemotherapy, the mechanism by which HMGA2 exerts these effects is unknown. A very common finding in HMGA2-high cancers is the under-expression of let-7. This is not unexpected, given let-7's natural role in the regulation of HMGA2. However, many cancers are found with normal levels of let-7 that are also HMGA2 high. Many of these cancers express the normal HMGA2 protein, but the mature mRNA transcript is truncated, missing a portion of the 3'UTR that contains the critical let-7 complementary regions. Without these, let-7 is unable to bind to HMGA2 mRNA, and, thus, is unable to repress it. The truncated mRNAs may arise from a
chromosomal translocation In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes "balanced" and "unbalanced" translocation, with three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...
that results in loss of a portion of the HMGA2 gene.


ERCC1

Overexpressed HMGA2 may play a role in the frequent repression of
ERCC1 DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. Many aspects of these two gen ...
in cancers. The let-7a miRNA normally represses the ''HMGA2'' gene, and in normal adult tissues, almost no HMGA2 protein is present. (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. As shown by Borrmann et al., HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression. These authors noted that repression of ERCC1 (by HGMA2) can reduce DNA repair, leading to increased
genome instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or ...
. ERCC1 protein expression is reduced or absent in 84% to 100% of human
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
s. ERCC1 protein expression was also reduced in a diet-related mouse model of colon cancer. As indicated in the
ERCC1 DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. Many aspects of these two gen ...
article, however, two other epigenetic mechanisms of repression of ERCC1 also may have a role in reducing expression of ERCC1 (promoter
DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter (genetics), promoter, DNA methylati ...
and
microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
repression).


Chromatin immunoprecipitation

Genome-wide analysis of HMGA2 target genes was performed by
chromatin immunoprecipitation Chromatin immunoprecipitation (ChIP) is a type of immunoprecipitation experimental technique used to investigate the interaction between proteins and DNA in the cell. It aims to determine whether specific proteins are associated with specific genom ...
in a gastric cell line with overexpressed HMGA2, and 1,366 genes were identified as potential targets. The pathways they identified as associated with malignant neoplasia progression were the
adherens junction In cell biology, adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissues, usually more basa ...
pathway,
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...
signaling pathway,
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
,
p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
signaling pathway,
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
signaling pathway,
Notch signaling pathway The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animal, animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTC ...
, and
TGF beta signaling pathway The transforming growth factor beta (TGFβ) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis a ...
.


Non-homologous end joining DNA repair

Overexpression of HMGA2 delayed the release of
DNA-PKcs DNA-dependent protein kinase catalytic subunit, also known as DNA-PKcs, is an enzyme that plays a crucial role in repairing DNA double-strand breaks and has a number of other DNA housekeeping functions. In humans it is encoded by the gene designa ...
(needed for
non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
DNA repair) from double strand break sites. Overexpression of HMGA2 alone was sufficient to induce chromosomal aberrations, a hallmark of deficiency in NHEJ-mediated DNA repair. These properties implicate HMGA2 in the promotion of genome instability and tumorigenesis. showed that


Base excision repair pathway

HMGA2 protein can cleave DNA containing apurinic/apyrimidinic (AP) sites (is an AP lyase). In addition, this protein also possesses the related 5’-deoxyribosyl phosphate (dRP) lyase activity. An interaction between human
AP endonuclease Apurinic/apyrimidinic (AP) endonuclease is an enzyme that is involved in the DNA base excision repair pathway (BER). Its main role in the repair of damaged or mismatched nucleotides in DNA is to create a nick in the phosphodiester backbone of t ...
1 and HMGA2 in cancer cells has been demonstrated indicating that HMGA2 can be incorporated into the cellular
base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
(BER) machinery. Increased expression of HMGA2 increased BER, and allowed cells with increased HMGA2 to be resistant to
hydroxyurea Hydroxycarbamide, also known as hydroxyurea, is an antimetabolite medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fe ...
, a chemotherapeutic agent for solid tumors.


Interactions

HMGA2 has been shown to interact with PIAS3 and
NFKB1 Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the ''NFKB1'' gene. This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD pro ...
. The transport of HMGA2 to the nucleus is mediated by an interaction between its second AT-hook and importin-α2.


See also

* HMGA


References


Further reading

* * * * * * * * * * * * * * * * * *


External links

* * Ellensburg 13-year-old grapples with life at 7 feet 3 inches tall

{{Use dmy dates, date=April 2017 Transcription factors