MDM2 tuumoribiologiassa proto-onkogeeni

M.Cassandri (2017) 

MDM2 (RANBP2.tyyppinen , RING.motiivin omaava ei-transkriptiofaktori, joka ei toimi transkriptiossa. Siitä huolimatta MDM2 on hyvin tärkeä tuumoribiologiassa ja erittäin tutkittu. Sen tärkeys syövässä lukeutuu sen säätelyvaikutuksiin, joita sillä on tuumorisupressori p53:n aktiivisuuteen. Todellakin MDM2 voi säädellä p53- aktiivisuuta kolmella tavalla. Ensiksikin- koska MDM2 ilmentää E3- ubikitiiniligaasiaktiivisuutta, se voi ubikitinoida p53-proteiinin ja edistää sen proteosomaalista silppuroitumista. Toiseksi MDM2 voi tehdä interaktion p53-proteiinin kanssa estäen p53:n sitoutumisen kohdegeeneihin, jotka välittävät p53:n tuumorisupressorifunktiota. Kolmanneksi MDM2 sitoutuu p53:n N-terminaaliin edistäen p53:n translokoitumista sytoplasmaan ja siten blokeeraa p53:n kohdegeenien aktivoitumiseen. Kuva3f.

MDM2:n tärkeyden tumorigeneesissa ovat myös yliekspressiokokeet osoittaneet. Itse asiassa MDM2:n yliekspressoiminen indusoi spontaania tuumorimuodostusta. Lisäksi tehtiin analyysi 4000 potilaan 28 eri tuumorityypistä ja havaittiin että 7%:ssa ihmisten syövistä MDM2-geeni oli laajentunut ( amplified). Erityisesti amplifikoitumisprosentti oli noussut liposarkoomissa( yli 80%), osteosarkoomissa ( yli 16%), pehmytkudostuumoreissa (20%) ja ruokatorven syövissä (13%). Ihmisen kasvannaisista on osoitettu pistemutaatioita,jotka kohdistuvat sinkkisormiproteiiniin MDM2. In vitro- tutkimuksilla on osoitettu, että nämä mutaatiot rikkovat MDM2:n interaktion ribosomaalisten proteiinien L5 ja L11 kanssa ja kyvyn hajoittaa p53 proteiinia. MDM2 katsotaan mahdolliseksi terapioitten kohdemolekyyliksi, koska se on näin tärkeä. Wang et al. on tehnyt laajan katsauksen kolmesta yhdisteestä (RG7112, RG7388 ja SAR405838), jotka ilmentävät relevanttia antituumoriaktiivisuutta potilaissa, joilla on p53wt I-vaiheen kliinisissä kokeissa.

Ottaen huomioon,että näiden yhdisteiden anti-syöpävaikutus perustuu p53wt:n aktivaatioon ,niitten oletetaan olevan tehokkaita vain niissä tapauksissa, joissa potilalla on p53wt. (mutatoitumaton p53).

LISÄTIETOA MDM2 geenistä

MDM2 (12q15) proto-oncogene, https://www.ncbi.nlm.nih.gov/gene/4193
 HDMX, hdm2, ACTFS.
Preferred Names:E3 ubiquitin-protein ligase Mdm2
Names:
MDM2 oncogene, E3 ubiquitin protein ligase,
MDM2 proto-oncogene, E3 ubiquitin protein ligase,
Mdm2, p53 E3 ubiquitin protein ligase homolog,
Mdm2, transformed 3T3 cell double minute 2, p53 binding protein,
double minute 2, human homolog of; p53-binding protein,
oncoprotein Mdm2.

Related articles in PubMed

1. Renal Epithelioid Angiomyolipoma Undergoing Aggressive Clinical Outcome: The MDM2 Expression in Tumor Cells of Two Cases. Inoue C, et al. Tohoku J Exp Med, 2019 Feb. PMID 30799331
2. CP‑31398 attenuates endometrial cancer cell invasion, metastasis and resistance to apoptosis by downregulating MDM2 expression. Liu L, et al. Int J Oncol, 2019 Mar. PMID 30628640, Free PMC Article The EC cells treated with CP‑31398 or siRNA against MDM2 exhibited an increased apoptosis and a suppressed migration and invasion, corresponding to an increased expression of p53, p21, Bad, Bax, Cyt‑c and caspase‑3, as well as to a decreased expression of Bcl‑2, Cox‑2, MMP‑2 and MMP‑9. Moreover, treatment with CP‑31398 and siRNA against MDM2 further enhanced these effects.
3. Association between MDM2 SNP309 and endometrial cancer risk: A PRISMA-compliant meta-analysis. Zou X, et al. Medicine (Baltimore), 2018 Dec. PMID 30544386, Free PMC Article
4. The Study of MDM2 rs937283 Variant and Cancer Susceptibility in a Central Chinese Population. Chen B, et al. Technol Cancer Res Treat, 2018 Jan 1. PMID 30244662, Free PMC Article
5. Contribution of Murine Double Minute 2 Genotypes to Colorectal Cancer Risk in Taiwan. Yueh TC, et al. Cancer Genomics Proteomics, 2018 Sep-Oct. PMID 30194081, Free PMC Article

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GeneRIFs: Gene References Into Functions

1. Expression of murine double minute 2 (MDM2) is increased in Endometrial cancer (EC) tissues and cell lines. The EC cells treated with CP31398 or siRNA against MDM2 exhibit an increased apoptosis and a suppressed migration and invasion. Treatment with CP31398 and siRNA against MDM2 further enhance these effects.
2. Brain-specific angiogenesis inhibitor 1 (BAI1) prevents proto-oncogene Protein c-mdm2 (Mdm2)-mediated tumor supressor p53 (p53) polyubiquitination, and its loss substantially reduces p53 levels.
3. TRIM65 binds to the N-terminus of p53 tumor suppressor and thus competes with MDM2 for p53 binding.
4. Expression of MDM2 and Bcl2 was significantly up-regulated, while Bax was down-regulated in renal cell carcinoma as compared with normal kidney tissue.
5. The study shows complex interrelation between apoptosis and cell cycle regulating proteins (MDM2, BCL2 and Bax) in benign prostatic hyperplasia and prostate cancer.
6. role of TNFAIP8 in NSCLC proliferation and cisplatin chemoresistance that is mediated through the MDM2/p53 pathway
7. MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner. Abstract
   MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro. MDM2 induces ubiquitination of WRN and dramatically downregulates the levels of WRN protein in human cells. During DNA damage response, WRN is translocated to the nucleoplasm to facilitate its DNA repair functions; however, it is degraded by the MDM2-mediated ubiquitination pathway. Moreover, the senescent phenotype induced by DNA damage reagents, such as Etoposide, is at least in part mediated by MDM2-dependent WRN degradation as it can be significantly attenuated by ectopic expression of WRN. These results show that MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner.
8. H3K9ac was a specific target for Ras-ERK1/2 signaling pathway. H3K9 acetylation can be modulated by HDAC2 and MDM2-depedent degradation of PCAF. The revealed regulation provides a better understanding of Ras-ERK1/2 signaling in tumorigenesis.
9. this is the first study demonstrating that MDM2 could play an important role in the molecular mechanisms of recurrence/metastasis of Epithelioid angiomyolipoma.
10. High-level MDM2 amplification determined by FISH strongly favors dedifferentiated liposarcoma over malignant peripheral nerve sheath tumor.

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