Mechanoregulation of proliferation.
The proliferation of all nontransformed adherent cells is dependent upon the development of mechanical tension within the cell; however, little is known about the mechanisms by which signals regulated by mechanical tension are integrated with those regulated by growth factors. We show here that Skp2, a component of a ubiquitin ligase complex that mediates the degradation of several proteins that inhibit proliferation, is upregulated when increased mechanical tension develops in intact smooth muscle and that its upregulation is critical for the smooth muscle proliferative response to increased mechanical tension. Notably, whereas growth factors regulate Skp2 at the level of protein stability, we found that mechanical tension regulates Skp2 at the transcriptional level. Importantly, we demonstrate that the calcium-regulated transcription factor NFATc1 is a critical mediator of the effect of increased mechanical tension on Skp2 transcription. These findings identify Skp2 as a node at which signals from mechanical tension and growth factors are integrated to regulate proliferation, and they define calcium-NFAT-Skp2 signaling as a critical pathway in the mechanoregulation of proliferation.
Jiang
Xiaogang
X
Division of Urology and Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.
Austin
Paul F
PF
Niederhoff
Robert A
RA
Manson
Scott R
SR
Riehm
Jacob J
JJ
Cook
Brian L
BL
Pengue
Gina
G
Chitaley
Kanchan
K
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Weintraub
Steven J
SJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D016384:Consensus Sequence; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013314:Stress, Mechanical; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic
D036341:Intercellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins