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Cyclophilin B is really a major growth factor in breast milk

Open AccessPublished:January 12, 2022DOI:https://doi.org/10.1016/j.jbc.2021.101481
      Cyclophilin B (CypB) was first described and its sequence was reported by Spik et al. in 1991 (
      • Spik G.
      • Haendler B.
      • Delmas O.
      • Mariller C.
      • Chamoux M.
      • Maes P.
      • Tartar A.
      • Montreuil J.
      • Stedman K.
      • Kocher H.P.
      • Keller R.
      • Hiestand P.C.
      • Movva N.R.
      A novel secreted cyclophilin-like protein (SCYLP).
      ). These authors prepared and characterized recombinant CypB demonstrating that it had prolyl isomerase activity, which was inhibited by cyclosporin (
      • Spik G.
      • Haendler B.
      • Delmas O.
      • Mariller C.
      • Chamoux M.
      • Maes P.
      • Tartar A.
      • Montreuil J.
      • Stedman K.
      • Kocher H.P.
      • Keller R.
      • Hiestand P.C.
      • Movva N.R.
      A novel secreted cyclophilin-like protein (SCYLP).
      ). At that time, no mitogenic activity was observed for CypB. This may be because of the absence of glycosylation, incorrect folding, denaturation, or to the cellular model used in these initial exploratory experiments (3T3). We wish to report that an earlier unpublished study (
      • Delmas O.
      Les facteurs de croissance du lait de femme: isolement et caractérisation d’un facteur de croissance analogue à la cyclophiline; Thèse de doctorat, n° 282.
      ) showed that CypB has growth factor activity on CCL-39 cells at around 30 ng/ml, similar to EGF, acidic FGF, and basic FGF. The mitogenic activity of CypB was found to be inhibited by Cyclosporin A (CsA), which binds to CypB at about 0.8 mol per mol. Inhibition was complete when CsA was added at a 70-fold excess (FGF activity was not inhibited by CsA). From the data obtained, the initial concentration of CypB in milk is at least 25 ng/ml (EGF concentration has been reported in the range 24–37 ng/ml). CypB is therefore one of the major growth factors in breast milk, sensitive to CsA. More recently published reports indicate a role for cyclophilin A and CypB in cell growth and signal transduction (
      • Jin Z.-G.
      • Melaragno D.-F.L.
      • Haendeler J.
      • Sue Y.-A.
      • Lambeth J.D.
      • Berk B.C.
      Cyclophilin A is a secreted growth factor induced by oxidative stress.
      ,
      • Pakula R.
      • Melchior A.
      • Denys A.
      • Vanpuille C.
      • Mazurier J.
      • Allain F.
      Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis.
      ). But direct mitogenic activity has never been published. It may act through isomerization of a proline residue of p38MAPK (
      • Brichkina A.
      • Nguyen N.T.M.
      • Baskar R.
      • Wee S.
      • Gunaratne J.
      • Robinson R.C.
      • Bulavin D.V.
      Proline isomerization as a novel regulatory mechanism for p38MAPK activation and functions.
      ). CypB may play roles during lactation, innate development, or necrotizing enterocolitis.

      Conflict of interest

      The author declares no conflicts of interests with the contents of this article.

      References

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        • Haendler B.
        • Delmas O.
        • Mariller C.
        • Chamoux M.
        • Maes P.
        • Tartar A.
        • Montreuil J.
        • Stedman K.
        • Kocher H.P.
        • Keller R.
        • Hiestand P.C.
        • Movva N.R.
        A novel secreted cyclophilin-like protein (SCYLP).
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        Les facteurs de croissance du lait de femme: isolement et caractérisation d’un facteur de croissance analogue à la cyclophiline; Thèse de doctorat, n° 282.
        Université des Sciences et Techniques de Lille- Flandres-Artois, France1988
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        Cyclophilin A is a secreted growth factor induced by oxidative stress.
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        Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis.
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        • Brichkina A.
        • Nguyen N.T.M.
        • Baskar R.
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        Proline isomerization as a novel regulatory mechanism for p38MAPK activation and functions.
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      Linked Article

      • A novel secreted cyclophilin-like protein (SCYLP)
        Journal of Biological ChemistryVol. 266Issue 17
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          A novel cyclosporin A binding glycoprotein of 21 kDa was isolated from human milk by several steps of cation exchange chromatography. The corresponding gene was cloned from human T cells, expressed in Escherichia coli and the recombinant protein purified. The protein shares 58% amino acid identity with the cytosolic cyclophilin and is initially synthesized with a hydrophobic leader sequence. The cyclophilin-like protein has also peptidyl-prolyl cis/trans-isomerase activity, although less efficient, that is inhibited by cyclosporin A.
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