Removal of LIF (leukemia inhibitory factor) results in increased vitamin A (retinol) metabolism to 4-oxoretinol in embryonic stem cells

Lane, Michelle A.; Chen, Anne C.; Roman, Shaun D.; Derguini, Fadila; Gudas, Lorraine J.

doi:10.1073/pnas.96.23.13524

Cited by 58 publications

(69 citation statements)

References 33 publications

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“…Other retinoids, such as retinol and retinaldehyde, are very poor competitors, suggesting that they are unlikely to be natural substrates for these enzymes under normal physiological conditions. This observation is in contrast to a recent report suggesting that P450RAI (CYP26A) may be involved in the activation step of retinol (21). These similarities would suggest that, at least with respect to metabolic activity, these enzymes may be equivalent.…”

Section: Discussioncontrasting

confidence: 55%

Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism

White

Ramshaw²,

Taimi³

et al. 2000

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

219

183

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Retinoids, particularly all-trans-retinoic acid (RA), are potent regulators of cell differentiation, cell proliferation, and apoptosis. The role of all-trans-RA during development and in the maintenance of adult tissues has been well established. The control of all-trans-RA levels in cells and tissues is regulated by the balance between its biosynthesis and its catabolism to inactive metabolites. The cytochrome P450 enzyme P450RAI (herein renamed P450RAI-1) is partially responsible for this inactivation of all-trans-RA. In this report, we describe the identification, molecular cloning, and characterization of a second related enzyme, P450RAI-2, which is also involved in the specific inactivation of all-trans-RA. Transiently transfected P450RAI-2 can convert all-trans-RA to more polar metabolites including 4-oxo-, 4-OH-, and 18-OH-all-trans-RA. Competition experiments with other retinoids suggest that all-trans-RA is the preferred substrate. The high level of expression of P450RAI-2, particularly in the cerebellum and pons of human adult brain, suggests a unique role for this enzyme in the protection of specific tissues from exposure to retinoids.

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Section: Discussioncontrasting

confidence: 55%

Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism

White

Ramshaw²,

Taimi³

et al. 2000

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

219

183

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“…In addition, variations in the residual levels of retinoic acid may account for the variability of the phenotypic rescue. The present data do not exclude any possible role for 4-oxo-retinol 17,18 .…”

Section: And C)mentioning

confidence: 61%

Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development

et al. 2002

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).Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that acts in developing and adult tissues 1 . The Cyp26a1 (cytochrome p450, 26) protein metabolizes retinoic acid into more polar hydroxylated and oxidized derivatives 2,3 . Whether some of these derivatives are biologically active metabolites has been debated 4,5 . Cyp26a1 -/-mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess retinoic acid administration, indicating that human CYP26A1 may be essential in controlling retinoic acid levels during development 6,7 . This hypothesis suggests that the Cyp26a1 -/-phenotype could be rescued under conditions in which embryonic retinoic acid levels are decreased. We show that Cyp26a1 -/-mice are phenotypically rescued by heterozygous disruption of Aldh1a2 (also known as Raldh2), which encodes a retinaldehyde dehydrogenase responsible for the synthesis of retinoic acid during early embryonic development 8,9 . Aldh1a2 haploinsufficiency prevents the appearance of spina bifida and rescues the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in Cyp26a1 -/-mice. Thus, some of these double-mutant mice can reach adulthood. This study is the first report of a mutation acting as a dominant suppressor of a lethal morphogenetic mutation in mammals. We provide genetic evidence that ALDH1A2 and CYP26A1 activities concurrently establish local embryonic retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent spina bifida.

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“…The retinol concentration in human serum is 1-2 mM, and fetal bovine serum contains less than 20 nM (see Lane et al, 1999). Recently we obtained improved day 60 pregnancy rates after transfer to recipients of blastocysts derived from oocytes matured with 9-cis-RA (Hidalgo et al, 2003).…”

Section: Discussionmentioning

confidence: 84%

9‐cis‐retinoic acid during in vitro maturation improves development of the bovine oocyte and increases midkine but not IGF‐I expression in cumulus‐granulosa cells

Gómez

Royo

Duque

et al. 2003

Molecular Reproduction Devel

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The isomer 9-cis of retinoic acid (9-cis-RA) exerts a beneficial effect on bovine in vitro development when added to in vitro maturation (IVM) culture. In the present work, 9-cis-RA 5 nM was found to be stimulatory as opposed to 500 nM (toxic). Cumulus-oocyte complexes (COCs) were treated with the found physiological dose 9-cis-RA 5 nM, and the next determinations performed: (1) relative expression of midkine (MK) and IGF-I, by reverse transcriptasepolymerase chain reaction (RT-PCR), in cumulusgranulosa cells detached from oocytes; (2) cytoplasmic granular migration, by labeling of oocytes with fluoroscein isothiocyanate lectins; and (3) in vitro survival of blastocysts after vitrification and warming. Gene expression of MK was enhanced by 9-cis-RA, but not by 1% ethanol (vehicle). However, we did not detect IGF-I expression, both in dependence on or in the absence of 9-cis-RA acting on cumulus-granulosa cells. The ability of vitrified blastocysts to survive in vitro was not improved by 9-cis-RA. Nevertheless, since only blastocysts obtained from oocytes matured with serum survived, more factors should be considered when evaluating cryopreservation survival. The complete granular migration observed in oocytes matured with 9-cis-RA anticipates the gain in developmental competence of the oocyte, being MK probably involved in this beneficial effect. Mol. Reprod.

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Removal of LIF (leukemia inhibitory factor) results in increased vitamin A (retinol) metabolism to 4-oxoretinol in embryonic stem cells

Cited by 58 publications

References 33 publications

Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism

Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism

Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development

9‐cis‐retinoic acid during in vitro maturation improves development of the bovine oocyte and increases midkine but not IGF‐I expression in cumulus‐granulosa cells

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