Stress-activated protein kinases are negatively regulated by cell density

Lallemand, Dominique; Ham, Jonathan; Garbay, Serge; Bakiri, Latifa; Traincard, François; Jeannequin, Odile; Pfarr, Curt M.; Yaniv, Moshe

doi:10.1093/emboj/17.19.5615

Cited by 90 publications

(63 citation statements)

References 70 publications

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“…This result was con®rmed by using a second anti-c-Jun speci®c antiserum (Black et al, 1994, data not shown). The increase in total c-Jun levels is accompanied by an increase of phosphorylated c-Jun at ser 63, as shown by Western blot analysis ( Figure 2A2), using speci®c anti-phospho-c-Jun antiserum (Lallemand et al, 1998).…”

Section: Altered Expression Of Normal and Mutant H-ras During Mouse Tmentioning

confidence: 73%

High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model

et al. 2000

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Analysis of the functions of AP-1 transcription factor in cellular systems has shown its key role as a mediator of oncogenic signals. The employment of suitable animal model systems greatly facilitates the study of changes in the composition and activity of the AP-1 complex. Here, we have analysed the quantitative and qualitative changes of AP-1 at dierent stages of carcinogenesis in mouse skin cell lines, derived from tumours induced by chemical mutagens. The ®ndings of this study suggest that elevated AP-1 DNA binding and transactivation activity characterize the carcinoma cell lines, most notably the highly malignant spindle carcinomas. In addition, increased amounts and post-translational modi®cations of c-Jun, Fra-1, Fra-2 and ATF-2 proteins account for a high percentage of the increased AP-1 activity. Remarkably, high levels of phosphorylated ATF-2 protein were detected in malignant cell lines, indicating a novel role of ATF-2 in tumour progression. c-Jun and ATF-2 proteins are phosphorylated by highly active JNK kinases present in tumour cells. Finally, our results indicate distinct functions for dierent AP-1 components in the promotion and progression of mouse skin tumours. Oncogene (2000) 19, 4011 ± 4021.

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Section: Altered Expression Of Normal and Mutant H-ras During Mouse Tmentioning

confidence: 73%

High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model

et al. 2000

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“…5). Previous studies have shown both the attachment of cells and the level of ERK phosphorylation has a limited effect under the addition of actin cytoskeleton disruption agents (40). In addition, other researchers have found molecules that are important in the mechanotransduction cascade, including platelet-endothelial cell adhesion molecule 1 and vascular cell adhesion molecule 1, that also have a direct corelation with cytoskeletal integrity (41,42).…”

Section: Resultsmentioning

confidence: 99%

Defining the role of syndecan-4 in mechanotransduction using surface-modification approaches

Bellin

Kubicek

Frigault

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

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The ability of cells to respond to external mechanical stimulation is a complex and robust process involving a diversity of molecular interactions. Although mechanotransduction has been heavily studied, many questions remain regarding the link between physical stimulation and biochemical response. Of significant interest has been the contribution of the transmembrane proteins involved, and integrins in particular, because of their connectivity to both the extracellular matrix and the cytoskeleton. Here, we demonstrate the existence of a mechanically based initiation molecule, syndecan-4. We first demonstrate the ability of syndecan-4 molecules to support cell attachment and spreading without the direct extracellular binding of integrins. We also examine the distribution of focal adhesion-associated proteins through controlling surface interactions of beads with molecular specificity in binding to living cells. Furthermore, after adhering cells to elastomeric membranes via syndecan-4-specific attachments we mechanically strained the cells via our mechanical stimulation and polymer surface chemical modification approach. We found ERK phosphorylation similar to that shown for mechanotransductive response for integrin-based cell attachments through our elastomeric membrane-based approach and optical magnetic twisting cytometry for syndecan-4. Finally, through the use of cytoskeletal disruption agents, this mechanical signaling was shown to be actin cytoskeleton dependent. We believe that these results will be of interest to a wide range of fields, including mechanotransduction, syndecan biology, and cell-material interactions.T he biochemical response of cells to external mechanical stimulation has generated tremendous interest over the past decade. Of particular interest are the causative contributions of mechanotransductive transmembrane integrin molecules that link the extracellular matrix (ECM) to the cell interior and play a role in physiological response and molecular signaling within the cell. Recently, numerous exciting discoveries have evolved from these studies including the role of mechanotransduction in vascular physiology and atherogenesis, Src activation (Src phosphorylation/ activation under local mechanical stimulation), and the effect of matrix stiffness on stem cell differentiation (1-3). Mechanical stimulation has been shown to produce a wide range of cellular responses including the proteomic activation of the mitogenactivated protein kinase (MAPK) pathways in extracellular signalregulated kinases (ERKs), alterations of genomic expression profiles, and control of cell morphology, differentiation, and proliferation (4, 5). However, such research has focused primarily on the integrins as the mechanical signal initiator/transmembrane protein. Although other strain-sensitive proteins, such as mechanosensitive ion channels and protein kinase C, are known to be altered by mechanical stimulation, these responses are thought to occur downstream or be directly linked to the transmembrane proteininitiating...

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“…However, the complete pathways and significance of cell density signal transduction in mammalian cells is largely unexplored. High cell density has been noted to influence a variety of cellular phenomena, such as renal (Amsler, 1994), hepatic (Kojima et al, 2000) and epidermal keratinocyte (Lee et al, 1998b) differentiation, positive and negative transcriptional regulation (Singh et al, 1996;Hornyak et al, 2000;Lindon et al, 2001) and protein kinase and phosphatase activities (Ostman et al, 1994;Lallemand et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

von Hippel–Lindau protein complex is regulated by cell density

Mohan

Burk

2003

Oncogene

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Mutations in the von Hippel-Lindau (VHL) gene are involved in the VHL family cancer syndrome and sporadic renal cell carcinoma. Previous studies indicated that VHL-induced growth arrest required high cell density and growth on extracellular matrix. In the present study, VHL protein (pVHL) levels were observed to be dramatically increased in cells grown to high cell density compared to cells grown at low cell density. Reverse transcription-polymerase chain reaction and Northern blot analysis indicated that VHL mRNA levels were equivalent in sparse and dense cells. The pVHL was rapidly degraded when cell-cell contact was disturbed by trypsinization or EDTA release. Treatment of cells with a proteasome inhibitor blocked the degradation of pVHL. Using a set of VHL deletions fused to GFP, a cell densitydependent region (CDDR) was identified and localized to the c-terminus of pVHL. In addition, other members of the VBC protein complex also showed a cell densitydependent regulation similar to pVHL. Cell density regulation of VHL did not require elongin binding and density-dependent regulation of other VBC components was not dependent on pVHL. In addition, hypoxia inducible factor-2a protein levels were elevated in sparse cells with low levels of pVHL and reduced or absent in confluent cells containing abundant VHL. These results indicate that pVHL levels and thus function are tightly regulated by cell-cell signaling. In addition, care must be taken when interpreting studies of VHL function and subcellular localization of cells grown at subconfluent conditions.

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Stress-activated protein kinases are negatively regulated by cell density

Cited by 90 publications

References 70 publications

High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model

High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model

Defining the role of syndecan-4 in mechanotransduction using surface-modification approaches

von Hippel–Lindau protein complex is regulated by cell density

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