p38 Inhibition ameliorates skin and skull abnormalities in
Fgfr2 Beare-Stevenson mice.

J 2012

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.

WANG, Y., X. ZHOU, K. OBEROI, R. PHELPS, R. COUWENHOVEN et. al.

Základní údaje

Originální název

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.

Autoři

WANG, Y. (840 Spojené státy), X. ZHOU (840 Spojené státy), K. OBEROI (840 Spojené státy), R. PHELPS (840 Spojené státy), R. COUWENHOVEN (840 Spojené státy), M. SUN (840 Spojené státy), A. REZZA (840 Spojené státy), G. HOLMES (840 Spojené státy), Ch.J. PERCIVAL (840 Spojené státy), J. FRIEDENTHAL (840 Spojené státy), Pavel KREJČÍ (203 Česká republika, garant, domácí), J.T. RICHTSMEIER (840 Spojené státy), D.L. HUSO (840 Spojené státy), Michael RENDL (840 Spojené státy) a E. WANG JABS (840 Spojené státy)

Vydání

The journal of clinical investigation, [New York, N.Y.], American Society for Clinical Investigation, 2012, 0021-9738

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30105 Physiology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 12.812

Kód RIV

RIV/00216224:14310/12:00065919

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1172/JCI62644

UT WoS

000304736300023

Klíčová slova anglicky

p38; skin; skull; FGFR2; Beare-Stevenson syndrome

Štítky

AKR, rivok, ZR

Změněno: 25. 4. 2014 14:05, Ing. Zdeňka Rašková

Anotace

V originále

Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.

Návaznosti

GAP305/11/0752, projekt VaV

Název: Molekulární základy FGFR3 signalingu v kostní dysplázii

Investor: Grantová agentura ČR, Molekulární základy FGFR3 signalingu v kostní dysplázii

GA301/09/0587, projekt VaV

Název: Nové dráhy FGFR3 signalingu v achondroplázii

Investor: Grantová agentura ČR, Nové dráhy FGFR3 signalingu v achondroplázii

MSM0021622430, záměr

Název: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Citovat

WANG, Y., X. ZHOU, K. OBEROI, R. PHELPS, R. COUWENHOVEN, M. SUN, A. REZZA, G. HOLMES, Ch.J. PERCIVAL, J. FRIEDENTHAL, Pavel KREJČÍ, J.T. RICHTSMEIER, D.L. HUSO, Michael RENDL a E. WANG JABS. p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. The journal of clinical investigation. [New York, N.Y.]: American Society for Clinical Investigation, 2012, roč. 122, č. 6, s. 2153-2164. ISSN 0021-9738. Dostupné z: https://dx.doi.org/10.1172/JCI62644.

@article{982600,
   author = {Wang, Y. and Zhou, X. and Oberoi, K. and Phelps, R. and Couwenhoven, R. and Sun, M. and Rezza, A. and Holmes, G. and Percival, Ch.J. and Friedenthal, J. and Krejčí, Pavel and Richtsmeier, J.T. and Huso, D.L. and Rendl, Michael and Wang Jabs, E.},
   article_location = {[New York, N.Y.]},
   article_number = {6},
   doi = {http://dx.doi.org/10.1172/JCI62644},
   keywords = {p38; skin; skull; FGFR2; Beare-Stevenson syndrome},
   language = {eng},
   issn = {0021-9738},
   journal = {The journal of clinical investigation},
   title = {p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.},
   volume = {122},
   year = {2012}
}

TY  - JOUR
ID  - 982600
AU  - Wang, Y. - Zhou, X. - Oberoi, K. - Phelps, R. - Couwenhoven, R. - Sun, M. - Rezza, A. - Holmes, G. - Percival, Ch.J. - Friedenthal, J. - Krejčí, Pavel - Richtsmeier, J.T. - Huso, D.L. - Rendl, Michael - Wang Jabs, E.
PY  - 2012
TI  - p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
JF  - The journal of clinical investigation
VL  - 122
IS  - 6
SP  - 2153-2164
EP  - 2153-2164
PB  - American Society for Clinical Investigation
SN  - 00219738
KW  - p38
KW  - skin
KW  - skull
KW  - FGFR2
KW  - Beare-Stevenson syndrome
N2  - Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.
ER  -

WANG, Y., X. ZHOU, K. OBEROI, R. PHELPS, R. COUWENHOVEN, M. SUN, A. REZZA, G. HOLMES, Ch.J. PERCIVAL, J. FRIEDENTHAL, Pavel KREJČÍ, J.T. RICHTSMEIER, D.L. HUSO, Michael RENDL a E. WANG JABS. p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. \textit{The journal of clinical investigation}. [New York, N.Y.]: American Society for Clinical Investigation, 2012, roč.~122, č.~6, s.~2153-2164. ISSN~0021-9738. Dostupné z: https://dx.doi.org/10.1172/JCI62644.

Podrobný výpis o publikaci