Mechanoregulation of Proliferation

Abstract

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.Cellular proliferation is regulated by (i) soluble factors, (ii) adhesion to the extracellular matrix, and (iii) the mechanical tension within the cytoskeleton. Although most studies of the regulation of proliferation have focused on the role of soluble factors and adhesion, it is clear that the role of the mechanical tension within the cytoskeleton is of equal importance. In fact, the proliferation of all nontransformed adherent cells is dependent upon the development of mechanical tension (21).The level of mechanical tension within the cytoskeleton is determined by three factors: (i) the tractional force generated by the cytoskeleton, (ii) the compliance of the extracellular matrix, and (iii) any pulling force transmitted through the extracellular matrix to the cell. These three factors are likely to have a critical regulatory role in every nonhematologic process in which proliferation occurs. Indeed, it has been noted that the sharp differences in the tissue patterns that arise across distances of less than a micrometer during organogenesis, tissue remodeling, and tissue repair cannot be attributed solely to gradients of soluble growth factors. Instead, it has been proposed that it is the differential regulation of proliferation by localized differences in mechanical tension that in large part sculpts the micromorphology of developing, remodeling, and repairing tissues (21). Although many of the "upstream" components of the signal transduction pathways that serve to mediate the mechanoregulation of proliferation, such as integrins, focal adhesion kinase, and the small GTPases RhoA and Rac, have been characterized (2), there is little known about those components that serve to couple mechanical signaling directly to the central cell cycle regulatory machinery.To begin to identify such "downstream" components of the signal transduc...

Regional dependency of the vascular smooth muscle cell contribution to the mechanical properties of the pig ascending aortic tissue

“…Beller et al (2008) found that the aortic root displacement increases the longitudinal stress in the AA at the outer curvature, which can explain the preferential axial VSMC orientation at this location. In addition, we found an increased VSMC density at the outer curvature, which again supports the hypothesis of a remodeling response to increased strain/stress, which has been shown to regulate the VSMC proliferation (Jiang et al, 2009).…”

Spatial constraints control cell proliferation in tissues

“…Interestingly, we observed that this control acts on a timescale similar to that of Yes-associated protein (YAP) inactivation after inhibition of cytoskeletal tension (35,38). Cytoskeletal tension therefore might serve as a mechanical read-out for spatial constraints to cell size and might be transduced to known regulators of growth, such as YAP, Skp2, or ERK (34,35,(38)(39)(40)(41)(42)(43). Although this system is faster than an average cell cycle, the 8-h delay in the proliferative response, together with the hysteresis-free adaption, would ensure that open space has to be available for a significant time to trigger an invasive response in a growing tissue and would prevent tissues from up-regulating cell proliferation in response to short-lived changes in their mechanical environment.…”

“…Moreover, studies in vivo have provided evidence that such a mechanism might control cell proliferation in tissue development and disease (39,(44)(45)(46)(47).…”

Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin

“…It has recently become recognized that Skp2 acts as a node governing the integration of signals from mechanical tension and growth factors to regulate cell proliferation (66). Such tension-related integration of signaling through Skp2 can impact fibrosis, which was demonstrated by therapeutic delivery of Skp2-targeting siRNAs to provide protection against fibrosis and reduce scarring in a glaucoma filtration surgery model (67).…”