Intracellular Signaling by 14-hydroxy-4,14-
            <i>Retro</i>
            -Retinol

Buck, Jochen; Derguini, Fadila; Levi, E.; Nakanishi, Koji; Hämmerling, Ulrich

doi:10.1126/science.1749937

Cited by 177 publications

(108 citation statements)

References 16 publications

(11 reference statements)

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“…Questions about other retinoid metabolites remain, however, including the didehydroretinoids found in chick embryos, and retro-retinoids, a class of hydroxylated retinoids whose biological activities are apparently not mediated by nuclear receptors [12][13][14] . Perhaps most enigmatic is the role of 9-cis retinoic acid, a high-affinity ligand for RXR, whose existence in vivo has been questioned because of difficulties in extracting it from tissues 2,15 .…”

Section: The Model Morphogen?mentioning

confidence: 99%

Retinoid metabolism: a balancing act

Perlmann

2002

Nat Genet

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Section: The Model Morphogen?mentioning

confidence: 99%

Retinoid metabolism: a balancing act

Perlmann

2002

Nat Genet

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“…The RAR activators from the acidified ether extracts of serum described here may support both ATRA and retinol as circulating effectors ( Figure 2B). Activators more polar than retinol could be hydroxylated metabolites such as 14-hydroxy-4,14-retro-retinol (Buck et al, 1991) and 13,14-dihydroxyretinol that would likely have retention times less than that of retinol (Derguini et al, 1995). Description of the ATRA metabolites 4-oxo-retinoic acid and 3,4-didehydro-retinoic acid as RAR inducers may also support this hypothesis (Allenby et al, 1993;Pijnappel et al, 1993).…”

Section: Phytol Metabolites As Transcriptional Signalsmentioning

confidence: 74%

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.

Kitareewan

Burka

Tomer

et al. 1996

MBoC

179

135

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RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 ,uM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytenic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced[3H]-9cRA from RXR with Ki values of 4 ,uM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways.

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“…Retinol is metabolized by cells to physiological derivatives (2), including 11-cis-retinal involved in vision (3), retinoic acids that induce differentiation in a variety of systems (4), and three signaling molecules, 14-hydroxy-4,14-retro-retinol (14-HRR) (5,6), anhydroretinol (AR) (7)(8)(9), and 13,14-dihydroxyretinol (DHR) (10). Of the retinoids, 14-HRR, DHR, and retinol, at least one is required in T lymphocyte activation (6,10,11) and for the growth of B lymphoblastoid (5,6,10,12,13) and HL-60 (8) cells when these cells are cultured in serum-free medium.…”

Section: Mammalian Sera Contain 1-2 M Vitamin a (Retinol) (1)mentioning

confidence: 99%

Vitamin A in serum is a survival factor for fibroblasts

Chen

Derguini

Buck

1997

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

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Murine 3T3 cells arrest in a quiescent, nondividing state when transferred into medium containing little or no serum. Within the first day after transfer, fibroblasts can be activated to proliferate by platelet-derived growth factor (PDGF) alone; cells starved longer than 1 day, however, are activated only by serum. We demonstrate that endogenous vitamin A (retinol) or retinol supplied by serum prevents cell death and that retinol, in combination with PDGF, can fully replace serum in activating cells starved longer than 1 day. The physiological retinol derivative 14-hydroxy-4,14-retroretinol, but not retinoic acid, can replace retinol in rescuing or activating 3T3 cells. Anhydroretinol, another physiological retinol metabolite that acts as a competitive antagonist of retinol, blocks cell activation by serum, indicating that retinol is a necessary component of serum. It previously has been proposed that activation of 3T3 cells requires two factors in serum, an activation factor shown to be PDGF and an unidentified survival factor. We report that retinol is the survival factor in serum.Mammalian sera contain 1-2 M vitamin A (retinol) (1). Retinol is metabolized by cells to physiological derivatives (2), including 11-cis-retinal involved in vision (3), retinoic acids that induce differentiation in a variety of systems (4), and three signaling molecules, 14-hydroxy-4,14-retro-retinol (14-HRR) (5, 6), anhydroretinol (AR) (7-9), and 13,14-dihydroxyretinol (DHR) (10). Of the retinoids, 14-HRR, DHR, and retinol, at least one is required in T lymphocyte activation (6, 10, 11) and for the growth of B lymphoblastoid (5, 6, 10, 12, 13) and HL-60 (8) cells when these cells are cultured in serum-free medium. AR competitively inhibits the growth-supportive effects of 14-HRR, DHR, or retinol (7-10). The enzyme, retinol dehydratase, which converts retinol to AR in the moth Spodoptera frugiperda recently has been purified, cloned, and expressed (14).When deprived of serum, NIH 3T3 cells arrest in a nondividing, quiescent state (15, 16). Proliferation of cells starved for 1 day is reportedly stimulated by platelet-derived growth factor (PDGF) (17), fibroblast growth factor (18), epidermal growth factor (EGF) (19), and phorbol ester (20); however, cells starved longer can be activated only by serum (21). We show in this study that retinol in serum and its intracellular derivative, 14-HRR, play an essential role in 3T3 cell activation. Whereas PDGF and EGF are activation factors and initiate the cell cycle, retinol and 14-HRR ensure cell cycle progression by preventing cell death. METHODSCell Activation Assays. NIH 3T3 cells (American Type Culture Collection) plated in 96-well microtiter plates in 100 l͞well of DMEM containing 10% calf serum (Colorado Serum, Denver) were grown to almost confluency, then were arrested by starvation in 150 l͞well of DMEM containing 0.5% calf serum. Cells were starved for 2 days before the assay unless mentioned otherwise. Resting cells were treated with assay reagents in 200 l͞well of RPMI med...

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Intracellular Signaling by 14-hydroxy-4,14- Retro -Retinol

Cited by 177 publications

References 16 publications

Retinoid metabolism: a balancing act

Retinoid metabolism: a balancing act

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.

Vitamin A in serum is a survival factor for fibroblasts

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