Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 Submitted 13 October 2003 ; accepted in final form 5 April 2004 Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, b...
Gespeichert in:
| Veröffentlicht in: | American Journal of Physiology: Cell Physiology 2004-08, Vol.287 (2), p.C494-C499 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | C499 |
|---|---|
| container_issue | 2 |
| container_start_page | C494 |
| container_title | American Journal of Physiology: Cell Physiology |
| container_volume | 287 |
| creator | Taniyama, Yoshihiro Ushio-Fukai, Masuko Hitomi, Hirofumi Rocic, Petra Kingsley, Michael J Pfahnl, Chun Weber, David S Alexander, R. Wayne Griendling, Kathy K |
| description | Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322
Submitted 13 October 2003
; accepted in final form 5 April 2004
Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.
mitogen-activated protein kinase; reactive oxygen species
Address for reprint requests and other correspondence: K. K. Griendling, Emory Univ., Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322 (E-mail: kgriend{at}emory.edu ). |
| doi_str_mv | 10.1152/ajpcell.00439.2003 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1152_ajpcell_00439_2003</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>66678036</sourcerecordid><originalsourceid>FETCH-LOGICAL-c453t-863ce7bb37ceac4c5d80ba51f8b20e36694285cea6e253a889019adceaa7e02f3</originalsourceid><addsrcrecordid>eNp1kE9P4zAQxS3ECkrhC3BAPnFL1__jHKsK2GpBu1qVs-U4TmtI4hAnsP32OG2BE9JIM5r5vafRA-ASoxnGnPzUT62xVTVDiNFsRhCiR2ASDyTBXNBjMEFU0ERgRk_BWQhPKIJEZCfgFHMkGUv5BKz_-cpCX8KWSvgw__sb6qbYDbESAl0TF2vne9uEOC-XiWuKwdgCzp97qE3vXnXvfDOCrzqYodIdDLX3_QbWQzDRfPwxnIMfpa6CvTj0KXi8vVktfiX3f-6Wi_l9YhinfSIFNTbNc5oaqw0zvJAo1xyXMifIUiEyRiSPN2EJp1rKDOFMF3GhU4tISafgeu_bdv5lsKFXtQvjB7qxfghKCJHKMZcpIHvQdD6Ezpaq7Vytu63CSI3xqkO8ahevGuONoquD-5DXtviSHPKMQLIHNm69eXOdVe1mG5yv_Hr7aUhkqohasIxFPvuevx2qamX_9x_CL51qi5K-AzrxnAY</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>66678036</pqid></control><display><type>article</type><title>Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells</title><source>MEDLINE</source><source>American Physiological Society</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Taniyama, Yoshihiro ; Ushio-Fukai, Masuko ; Hitomi, Hirofumi ; Rocic, Petra ; Kingsley, Michael J ; Pfahnl, Chun ; Weber, David S ; Alexander, R. Wayne ; Griendling, Kathy K</creator><creatorcontrib>Taniyama, Yoshihiro ; Ushio-Fukai, Masuko ; Hitomi, Hirofumi ; Rocic, Petra ; Kingsley, Michael J ; Pfahnl, Chun ; Weber, David S ; Alexander, R. Wayne ; Griendling, Kathy K</creatorcontrib><description>Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322
Submitted 13 October 2003
; accepted in final form 5 April 2004
Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.
mitogen-activated protein kinase; reactive oxygen species
Address for reprint requests and other correspondence: K. K. Griendling, Emory Univ., Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322 (E-mail: kgriend{at}emory.edu ).</description><identifier>ISSN: 0363-6143</identifier><identifier>EISSN: 1522-1563</identifier><identifier>DOI: 10.1152/ajpcell.00439.2003</identifier><identifier>PMID: 15084475</identifier><language>eng</language><publisher>United States</publisher><subject>Angiotensin II - pharmacology ; Animals ; Aorta, Thoracic - cytology ; Cells, Cultured ; Intracellular Signaling Peptides and Proteins ; Male ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - physiology ; Mitogen-Activated Protein Kinases - metabolism ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - enzymology ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species - metabolism ; Vasoconstrictor Agents - pharmacology</subject><ispartof>American Journal of Physiology: Cell Physiology, 2004-08, Vol.287 (2), p.C494-C499</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c453t-863ce7bb37ceac4c5d80ba51f8b20e36694285cea6e253a889019adceaa7e02f3</citedby><cites>FETCH-LOGICAL-c453t-863ce7bb37ceac4c5d80ba51f8b20e36694285cea6e253a889019adceaa7e02f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15084475$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Taniyama, Yoshihiro</creatorcontrib><creatorcontrib>Ushio-Fukai, Masuko</creatorcontrib><creatorcontrib>Hitomi, Hirofumi</creatorcontrib><creatorcontrib>Rocic, Petra</creatorcontrib><creatorcontrib>Kingsley, Michael J</creatorcontrib><creatorcontrib>Pfahnl, Chun</creatorcontrib><creatorcontrib>Weber, David S</creatorcontrib><creatorcontrib>Alexander, R. Wayne</creatorcontrib><creatorcontrib>Griendling, Kathy K</creatorcontrib><title>Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells</title><title>American Journal of Physiology: Cell Physiology</title><addtitle>Am J Physiol Cell Physiol</addtitle><description>Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322
Submitted 13 October 2003
; accepted in final form 5 April 2004
Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.
mitogen-activated protein kinase; reactive oxygen species
Address for reprint requests and other correspondence: K. K. Griendling, Emory Univ., Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322 (E-mail: kgriend{at}emory.edu ).</description><subject>Angiotensin II - pharmacology</subject><subject>Animals</subject><subject>Aorta, Thoracic - cytology</subject><subject>Cells, Cultured</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - enzymology</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>Phosphorylation</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Vasoconstrictor Agents - pharmacology</subject><issn>0363-6143</issn><issn>1522-1563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE9P4zAQxS3ECkrhC3BAPnFL1__jHKsK2GpBu1qVs-U4TmtI4hAnsP32OG2BE9JIM5r5vafRA-ASoxnGnPzUT62xVTVDiNFsRhCiR2ASDyTBXNBjMEFU0ERgRk_BWQhPKIJEZCfgFHMkGUv5BKz_-cpCX8KWSvgw__sb6qbYDbESAl0TF2vne9uEOC-XiWuKwdgCzp97qE3vXnXvfDOCrzqYodIdDLX3_QbWQzDRfPwxnIMfpa6CvTj0KXi8vVktfiX3f-6Wi_l9YhinfSIFNTbNc5oaqw0zvJAo1xyXMifIUiEyRiSPN2EJp1rKDOFMF3GhU4tISafgeu_bdv5lsKFXtQvjB7qxfghKCJHKMZcpIHvQdD6Ezpaq7Vytu63CSI3xqkO8ahevGuONoquD-5DXtviSHPKMQLIHNm69eXOdVe1mG5yv_Hr7aUhkqohasIxFPvuevx2qamX_9x_CL51qi5K-AzrxnAY</recordid><startdate>20040801</startdate><enddate>20040801</enddate><creator>Taniyama, Yoshihiro</creator><creator>Ushio-Fukai, Masuko</creator><creator>Hitomi, Hirofumi</creator><creator>Rocic, Petra</creator><creator>Kingsley, Michael J</creator><creator>Pfahnl, Chun</creator><creator>Weber, David S</creator><creator>Alexander, R. Wayne</creator><creator>Griendling, Kathy K</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20040801</creationdate><title>Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells</title><author>Taniyama, Yoshihiro ; Ushio-Fukai, Masuko ; Hitomi, Hirofumi ; Rocic, Petra ; Kingsley, Michael J ; Pfahnl, Chun ; Weber, David S ; Alexander, R. Wayne ; Griendling, Kathy K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c453t-863ce7bb37ceac4c5d80ba51f8b20e36694285cea6e253a889019adceaa7e02f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Angiotensin II - pharmacology</topic><topic>Animals</topic><topic>Aorta, Thoracic - cytology</topic><topic>Cells, Cultured</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - enzymology</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>Phosphorylation</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Vasoconstrictor Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Taniyama, Yoshihiro</creatorcontrib><creatorcontrib>Ushio-Fukai, Masuko</creatorcontrib><creatorcontrib>Hitomi, Hirofumi</creatorcontrib><creatorcontrib>Rocic, Petra</creatorcontrib><creatorcontrib>Kingsley, Michael J</creatorcontrib><creatorcontrib>Pfahnl, Chun</creatorcontrib><creatorcontrib>Weber, David S</creatorcontrib><creatorcontrib>Alexander, R. Wayne</creatorcontrib><creatorcontrib>Griendling, Kathy K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>American Journal of Physiology: Cell Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Taniyama, Yoshihiro</au><au>Ushio-Fukai, Masuko</au><au>Hitomi, Hirofumi</au><au>Rocic, Petra</au><au>Kingsley, Michael J</au><au>Pfahnl, Chun</au><au>Weber, David S</au><au>Alexander, R. Wayne</au><au>Griendling, Kathy K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells</atitle><jtitle>American Journal of Physiology: Cell Physiology</jtitle><addtitle>Am J Physiol Cell Physiol</addtitle><date>2004-08-01</date><risdate>2004</risdate><volume>287</volume><issue>2</issue><spage>C494</spage><epage>C499</epage><pages>C494-C499</pages><issn>0363-6143</issn><eissn>1522-1563</eissn><abstract>Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322
Submitted 13 October 2003
; accepted in final form 5 April 2004
Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.
mitogen-activated protein kinase; reactive oxygen species
Address for reprint requests and other correspondence: K. K. Griendling, Emory Univ., Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322 (E-mail: kgriend{at}emory.edu ).</abstract><cop>United States</cop><pmid>15084475</pmid><doi>10.1152/ajpcell.00439.2003</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0363-6143 |
| ispartof | American Journal of Physiology: Cell Physiology, 2004-08, Vol.287 (2), p.C494-C499 |
| issn | 0363-6143 1522-1563 |
| language | eng |
| recordid | cdi_crossref_primary_10_1152_ajpcell_00439_2003 |
| source | MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Angiotensin II - pharmacology Animals Aorta, Thoracic - cytology Cells, Cultured Intracellular Signaling Peptides and Proteins Male MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology Mitogen-Activated Protein Kinases - metabolism Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - enzymology p38 Mitogen-Activated Protein Kinases Phosphorylation Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley Reactive Oxygen Species - metabolism Vasoconstrictor Agents - pharmacology |
| title | Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T21%3A12%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Role%20of%20p38%20MAPK%20and%20MAPKAPK-2%20in%20angiotensin%20II-induced%20Akt%20activation%20in%20vascular%20smooth%20muscle%20cells&rft.jtitle=American%20Journal%20of%20Physiology:%20Cell%20Physiology&rft.au=Taniyama,%20Yoshihiro&rft.date=2004-08-01&rft.volume=287&rft.issue=2&rft.spage=C494&rft.epage=C499&rft.pages=C494-C499&rft.issn=0363-6143&rft.eissn=1522-1563&rft_id=info:doi/10.1152/ajpcell.00439.2003&rft_dat=%3Cproquest_cross%3E66678036%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=66678036&rft_id=info:pmid/15084475&rfr_iscdi=true |