The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: A focus on ADAM12

Aghababaei, Mahroo; Beristain, Alexander G.

doi:10.1016/j.placenta.2014.12.016

Cited by 10 publications

(5 citation statements)

References 99 publications

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“…4, the broad-range ADAM and MMP inhibitors Batimastat and Marimastat and the MMP inhibitor GM6001 clearly inhibited HEMO release in the supernatant to various extents and in a dose-dependent manner, with visible accumulation of the nonsecreted form in the cell lysates. These experiments suggest that, in vivo, HEMO shedding could be driven by one or several metalloproteinases known to be present notably in placental cells (23)(24)(25). Fig.…”

Section: Syn-car1mentioning

confidence: 71%

HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

Heidmann

Béguin

Paternina

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Capture of retroviral envelope genes is likely to have played a role in the emergence of placental mammals, with evidence for multiple, reiterated, and independent capture events occurring in mammals, and be responsible for the diversity of present day placental structures. Here, we uncover a full-length endogenous retrovirus envelope protein, dubbed HEMO [human endogenous MER34 (mediumreiteration-frequency-family-34) ORF], with unprecedented characteristics, because it is actively shed in the blood circulation in humans via specific cleavage of the precursor envelope protein upstream of the transmembrane domain. At variance with previously identified retroviral envelope genes, its encoding gene is found to be transcribed from a unique CpG-rich promoter not related to a retroviral LTR, with sites of expression including the placenta as well as other tissues and rather unexpectedly, stem cells as well as reprogrammed induced pluripotent stem cells (iPSCs), where the protein can also be detected. We provide evidence that the associated retroviral capture event most probably occurred >100 Mya before the split of Laurasiatheria and Euarchontoglires, with the identified retroviral envelope gene encoding a full-length protein in all simians under purifying selection and with similar shedding capacity. Finally, a comprehensive screen of the expression of the gene discloses high transcript levels in several tumor tissues, such as germ cell, breast, and ovarian tumors, with in the latter case, evidence for a histotype dependence and specific protein expression in clear-cell carcinoma. Altogether, the identified protein could constitute a "stemness marker" of the normal cell and a possible target for immunotherapeutic approaches in tumors.HERV | endogenous retrovirus | envelope protein | placenta | development | stem cells | tumors E ndogenous retroviral sequences represent ∼8% of the human genome. These sequences [called human endogenous retroviruses (HERVs)] share strong similarities with present day retroviruses and are the proviral remnants of ancestral germ-line infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner (1-3). The >30,000 proviral copies found in the human genome can be grouped into about 80 distinct families, with most of these elements being nonprotein-coding because of the accumulation of mutations, insertions, deletions, and/or truncations (4, 5). However, some retroviral genes have retained a coding capacity, and some of them have even been diverted by remote primate ancestors for a physiological role. The so-called "syncytins," namely syncytin-1 and -2 in humans, are retroviral envelope (env) genes captured 25 and 40 Mya, respectively, with a full-length proteincoding sequence, a fusogenic activity, and strong placental expression (6-9). These genes have been shown to be involved in placenta formation, with their fusogenic activity contributing to the formation of the syncytiotrophoblast (ST) at the maternofetal interface as a result of the syncytin-mediated...

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Section: Syn-car1mentioning

confidence: 71%

HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

Heidmann

Béguin

Paternina

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, we cannot distinguish between a direct MMP15 effect and an indirect effect through activation of pro-MMP2. 40 Likewise, the activity of other ECM-degrading enzymes, for example, ADAMs, cathepsins and serine proteases, 5,6 could also explain why trophoblast outgrowth was not completely abrogated upon MMP15 silencing. Interestingly, MMP15 inhibits apoptosis in several tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…eCTB invasive potential is determined by their capacity to degrade the surrounding extracellular matrix (ECM). Therefore, eCTB express a broad repertoire of proteases, including serine‐proteases, cathepsins, a disintegrin and metalloproteinases (ADAMs), and matrix metalloproteinases (MMPs) 5,6 . The latter are a family of 23 endopeptidases whose substrates include the majority of ECM components 7 .…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, eCTB express a broad repertoire of proteases, including serine-proteases, cathepsins, a disintegrin and metalloproteinases (ADAMs), and matrix metalloproteinases (MMPs). 5,6 The latter are a family of 23 endopeptidases whose substrates include the majority of ECM components. 7 MMPs are synthesized as zymogens and can either be secreted or anchored to the plasma membrane, that is, membrane-type (MT)-MMPs.…”

Section: Introductionmentioning

confidence: 99%

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Matrix metalloproteinase 15 plays a pivotal role in human first trimester cytotrophoblast invasion and is not altered by maternal obesity

et al. 2020

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“…MMP‐2 and MMP‐9 are defined to induce trophoblast invasion and play crucial roles in human implantation . Besides MMPs, a disintegrin and metalloproteinase (ADAM) family member ADAM12 and ADAMTS also plays a critical role in the regulation of trophoblast invasion . Taken together, as the crosslinking and degradation enzymes all play critical roles during decidualization, the balanced collaboration among these enzymes might provide the dynamic environment for embryo adhesion and development in different phases during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of lysyl oxidase‐mediated extracellular matrix remodeling during mouse decidualization

Yan

Song

et al. 2017

FEBS Letters

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The establishment of decidualization is a prerequisite of successful pregnancy. Lysyl oxidase (Lox) is a copper-containing amine oxidase which catalyzes cross-linking of collagen and elastin in the ECM. Lox is expressed in the subluminal stroma surrounding the implanting blastocyst on day 5 of pregnancy. From days 6 to 8, the signals for Lox mRNA and protein are strongly detected in the decidual cells. The expression of Lox is under the control of estrogen via the GSK-3β/β-catenin/c-myc pathway. Dtprp is decreased by the inhibition of Lox activity. Furthermore, the inhibition of Lox activity decreases stromal cell migration and embryo adhesion. Our findings highlight the crucial role of Lox in endometrial stromal cells and deepen our understanding of decidualization.

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The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: A focus on ADAM12

Cited by 10 publications

References 99 publications

HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

Matrix metalloproteinase 15 plays a pivotal role in human first trimester cytotrophoblast invasion and is not altered by maternal obesity

Molecular characterization of lysyl oxidase‐mediated extracellular matrix remodeling during mouse decidualization

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