Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) 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 ''MTDH''

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

MTDH (AEG-1) is involved in

HIF-1alpha Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the ''HIF1A'' gene. The Nobel Prize in Physiology or Medicine 2019 was awarded ...

mediated

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

. MTDH also interacts with

SND1 Staphylococcal nuclease domain-containing protein 1 also known as 100 kDa coactivator or Tudor domain-containing protein 11 (TDRD11) is a protein that in humans is encoded by the ''SND1'' gene. SND1 is a main component of RISC complex and plays a ...

and involved in

RNA-induced silencing complex The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) ...

(RISC) and plays very important role in RISC and

miRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...

functions. MTDH has been shown to interact with spliceosome proteins in the cell nucleus and regulate the process of alternative splicing. MTDH induces an oncogene called Late SV40 factor (LSF/

TFCP2 Alpha-globin transcription factor CP2 is a protein that in humans is encoded by the ''TFCP2'' gene. TFCP2 is also called Late SV40 factor (LSF) and it is induced by well known oncogene AEG-1. LSF also acts as an oncogene in hepatocellular carcin ...

) which is involved in

thymidylate synthase Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleo ...

(TS) induction and DNA biosynthesis synthesis. Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (

MMP9 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extrace ...

Clinical significance

MTDH acts as an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

, malignant

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

and

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

. It is highly expressed in these cancers and helps in their progression and development. It is induced by

c-Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...

oncogene and plays an important role in anchorage independent growth of cancer cells (

metastasis Metastasis is a pathogenic agent's spread 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, then, ...

). Elevated expression of MTDH, which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting

metastatic Metastasis is a pathogenic agent's spread 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, then, ...

seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

and reducing metastasis. MTDH has been shown to be overexpressed in

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

, where there is a shift towards a more cytoplasmic localisation, signalling a poor prognosis. In the nucleus of prostate cancer cells, MTDH has been shown to affect alternative splicing of genes such as CD44, which may also be associated with prostate cancer progression. LSF/

plays a multifaceted role in chemo resistance, EMT, allergic response, inflammation and

Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

. MTDH controls many hallmarks of oncogenes and cancer. MTDH/AEG-1 induces hepato steatosis in mouse liver. MTDH knockdown by artificial microRNA interference functions as a potential

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...

in breast cancer. Astrocyte elevated gene-1/MTDH undergoes

palmitoylation Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically lipid bilayer, memb ...

in normal and abnormal cell physiology. Biomaterial titanium substrata with microgrooves can alter MTDH expression in human primary cells.

Interactions

MTDH has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

Nucleolin Nucleolin is a protein that in humans is encoded by the ''NCL'' gene. Gene The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucl ...

, * NF-kB-p65 subunit,

Function

Clinical significance

Interactions

References

Further reading