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Sökning: WFRF:(Petrova Tatiana V.) > Palmdelphin Regulat...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00007753naa a2200721 4500
001oai:DiVA.org:uu-467403
003SwePub
008220218s2021 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:148715246
009oai:slubar.slu.se:113991
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4674032 URI
0247 a https://doi.org/10.1161/CIRCULATIONAHA.121.0541822 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1487152462 URI
0247 a https://res.slu.se/id/publ/1139912 URI
040 a (SwePub)uud (SwePub)kid (SwePub)slu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Sainz-Jaspeado, Miguelu Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)migsa268
2451 0a Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium
264 1b Wolters Kluwer,c 2021
338 a electronic2 rdacarrier
520 a Background: PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis and predict severity of the disease.Methods: Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes.Results: ECs express the cytosolic PALMD-KKVI splice variant, which associated with RANGAP1 (RAN GTP hydrolyase activating protein 1). RANGAP1 regulates the activity of the GTPase RAN and thereby nucleocytoplasmic shuttling via XPO1 (Exportin1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently in gene regulation because of the effect on localization of transcriptional regulators. Changes in EC responsiveness on loss of PALMD expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in PALMD-deficient ECs, Palmd(-/-) mouse aorta, and human aortic valve samples derived from patients with calcific aortic valve stenosis. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in PALMD-silenced ECs.Conclusions: We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced PALMD expression provide a mechanistic underpinning for PALMD's contribution to calcific aortic valve stenosis pathology.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Kardiologi0 (SwePub)302062 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cardiac and Cardiovascular Systems0 (SwePub)302062 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Immunologi inom det medicinska området0 (SwePub)301102 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Immunology in the medical area0 (SwePub)301102 hsv//eng
653 a aortic valve stenosis
653 a endothelial cells
653 a nucleocytoplasmic transport
653 a palmdelphin
7001 a Smith, Ross O.u Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi4 aut0 (Swepub:uu)rossm781
7001 a Plunde, Oscaru Karolinska Institutet4 aut
7001 a Pawelzik, Sven-Christianu Karolinska Institutet4 aut
7001 a Jin, Yiu Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)jinyi632
7001 a Nordling, Sofia,d 1985-u Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)sofno833
7001 a Ding, Yindiu Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi4 aut0 (Swepub:uu)yindi780
7001 a Aspenström, Pontusu Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)pontaspe
7001 a Hedlund, Marieu Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi4 aut0 (Swepub:uu)mimmjoha
7001 a Bastianello, Giuliau Fdn Italiana Ric Sul Canc, IFOM FIRC, Inst Mol Oncol, Milan, Italy.;Univ Milan, Milan, Italy.4 aut
7001 a Ascione, Florau Fdn Italiana Ric Sul Canc, IFOM FIRC, Inst Mol Oncol, Milan, Italy.4 aut
7001 a Li, Qingsenu Fdn Italiana Ric Sul Canc, IFOM FIRC, Inst Mol Oncol, Milan, Italy.4 aut
7001 a Demir, Cansaran Saygiliu Univ Lausanne, Dept Oncol, Lausanne, Switzerland.;Ludwig Inst Canc Res Lausanne, Lausanne, Switzerland.4 aut
7001 a Fernando, Dineshu Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Skogens biomaterial och teknologi,Department of Forest Biomaterials and Technology4 aut0 (Swepub:slu)50319
7001 a Daniel, Geoffreyu Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Skogens biomaterial och teknologi,Department of Forest Biomaterials and Technology4 aut0 (Swepub:slu)47230
7001 a Franco-Cereceda, Andersu Karolinska Institutet4 aut
7001 a Kroon, Jeffreyu Univ Amsterdam, Dept Expt Vasc Med, Amsterdam Cardiovasc Sci, Amsterdam Univ Med Ctr, Amsterdam, Netherlands.4 aut
7001 a Foiani, Marcou Fdn Italiana Ric Sul Canc, IFOM FIRC, Inst Mol Oncol, Milan, Italy.;Univ Milan, Milan, Italy.4 aut
7001 a Petrova, Tatiana, Vu Univ Lausanne, Dept Oncol, Lausanne, Switzerland.;Ludwig Inst Canc Res Lausanne, Lausanne, Switzerland.4 aut
7001 a Kilimann, Manfred W.u Uppsala universitet,Institutionen för neurovetenskap,Max Planck Inst Expt Med, Dept Mol Neurobiol, Gottingen, Germany.4 aut0 (Swepub:uu)makil021
7001 a Back, Magnusu Karolinska Institutet4 aut
7001 a Claesson-Welsh, Lenau Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi4 aut0 (Swepub:uu)lcl04207
7102 a Uppsala universitetb Vaskulärbiologi4 org
7102 a Sveriges lantbruksuniversitet
7730 t Circulationd : Wolters Kluwerg 144:20, s. 1629-1645q 144:20<1629-1645x 0009-7322x 1524-4539
8564 u https://doi.org/10.1161/CIRCULATIONAHA.121.054182y Fulltext
8564 u https://uu.diva-portal.org/smash/get/diva2:1638917/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
8564 u https://pub.epsilon.slu.se/id/eprint/26278/contentsx primaryx Raw objectx freey FULLTEXT
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-467403
8564 8u https://doi.org/10.1161/CIRCULATIONAHA.121.054182
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:148715246
8564 8u https://res.slu.se/id/publ/113991

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