Extracellular matrix-dependent myosin dynamics during G1-S phase cell cycle progression in hepatocytes

Bhadriraju, Kiran; Hansen, Linda K.

doi:10.1016/j.yexcr.2004.06.033

Cited by 18 publications

(20 citation statements)

References 79 publications

(118 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4,6,33 Here, we found that MLCK inhibition prevents cyclin D1 expression at the mRNA and protein levels. This process could occur independently of actin because actin cytoskeleton breakdown inhibits ERK phosphorylation in hepatocytes, 31 whereas ML7 treatment did not in our study. In 3T3 cells, RhoK has also been reported to drive late G1 progression, leading to a more rapid progression in S phase in RhoKinhibited cells in parallel with strikingly early expression of cyclin D1.…”

Section: Discussioncontrasting

confidence: 64%

“…29,30 Furthermore, inhibition of MLCK was found to block DNA synthesis in hepatocytes cultured on high-density fibronectin. 31 In the current study, the involvement of MLCK and RhoK in late G1 phase progression was specified, and we evidenced the pathways involved in MLCK-dependent regulation of G1/S transition in proliferating hepatocytes. This effect was enforced by the establishment of a precise window, in late G1, in which inhibition of MLCK blocked hepatocyte progression.…”

mentioning

confidence: 53%

“…In contrast, an overexpression of cyclin D1 has been reported to be sufficient to allow hepatocyte progression in S phase in vitro 47 and in vivo. 48 In hepatocytes seeded on fibronectin, Bhadriraju and Hansen (2004) demonstrated that exogenous expression of cyclin D1 was sufficient to overcome DNA synthesis inhibition by MLCK inhibitor ML9. Discrepancies between results could be linked to experimental conditions: ERK phosphorylation was completely inhibited in the presence of ML9 on high-density fibronectin, whereas ERK signaling was never blocked by inhibition of MLCK in our experiments.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

An MLCK-dependent window in late G1 controls S phase entry of proliferating rodent hepatocytes via ERK-p70S6K pathway

et al. 2006

View full text Add to dashboard Cite

We show that MLCK (myosin light chain kinase) plays a key role in cell cycle progression of hepatocytes: either chemical inhibitor ML7 or RNA interference led to blockade of cyclin D1 expression and DNA replication, providing evidence that MLCK regulated S phase entry. Conversely, inhibition of RhoK by specific inhibitor Y27632 or RhoK dominant-negative vector did not influence progression in late G1 and S phase entry. Inhibition of either MLCK or RhoK did not block ERK1/2 phosphorylation, whereas MLCK regulated ERK2-dependent p70S6K activation. In addition, DNA synthesis was reduced in hepatocytes treated with p70S6K siRNA, demonstrating the key role played by the kinase in S phase entry. Interestingly, after the G1/S transition, DNA replication in S phase was no longer dependent on MLCK activity. We strengthened this result by ex vivo experiments and evidenced an MLCK-dependent window in late G1 phase of regenerating liver after two-thirds partial hepatectomy. In conclusion, our results underline an MLCK-dependent restriction point in G1/S transition, occurring downstream of ERK2 through the regulation of p70S6K activation, and highlighting a new signaling pathway critical for hepatocyte proliferation. T he G1 phase is a preparative step where cells temporally integrate complex signals from the microenvironment. At this time, the cells are able to switch between proliferation, differentiation or apoptosis, depending on extracellular matrix composition, cytokines, and cell-cell contacts. In the hepatocyte, a highly differentiated cell, cell cycle progression in vivo during liver regeneration is regulated by a sequential acquisition of complex signals depending on transduction pathway activation. 1-3 Primary cultures of hepatocytes are a powerful model in studying the precise sequence of events that are necessary for cell progression from a G0-like state to S phase. The model mimics the physiological process of hepatic regeneration after liver injury or partial hepatectomy. In this context, we have already demonstrated that epidermal growth factor (EGF) possesses two distinct and complementary effects on G1 phase hepatocytes. 4 First, the growth factor is a morphogen in early G1 phase by inducing controlled spreading of hepatocytes via integrin ␤1 regulation. Second, a mitogenic effect occurs in midlate G1 phase and allows hepatocytes to progress through a restriction point located two thirds of the way through G1 phase. [5][6][7] In addition, EGF promotes cell progression up to late G1. 7 In hepatocytes, EGF activates specific transduction pathways. MEK and PI3K signaling cascades are essential for progression past the G1/S checkpoint and hepatocyte progression to S phase. 8 They both control expression of cyclin D1, a key cell cycle protein that is upregulated in the pre-replicative phase of liver regeneration and in primary culture hepatocytes. 4,9,10 MLCK and RhoK, two kinases linked to the contractile apparatus, are known to be involved in the regulation of a wide range of cellular functions, including prol...

show abstract

Section: Discussioncontrasting

confidence: 64%

mentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

An MLCK-dependent window in late G1 controls S phase entry of proliferating rodent hepatocytes via ERK-p70S6K pathway

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Cyclin D1 mRNA and protein expression as well as associated kinase activity are low on collagen gel relative to collagen film. Similar results are obtained when hepatocytes are spread on high fibronectin density (proliferation) or low fibronectin density (cell cycle arrest) coatings (Bhadriraju and Hansen, 2004). In this context, we asked the question on how mitogen signals and extracellular matrix degradation are linked to promote cell cycle entry and progression of differentiated adult hepatocytes.…”

Section: Regulation Of the Cdk1 Expression And Activation Under The Csupporting

confidence: 54%

Regulation of the G1/S Transition in Adult Liver: Expression and Activation of the Cyclin Dependent Kinase Cdk1 in Differentiated Hepatocytes is Controlled by Extracellular Signals and is Crucial for Commitment to DNA Replication

Loyer¹,

Corlu²

2011

DNA Replication-Current Advances

View full text Add to dashboard Cite

“…Importantly, these effects are not shared by other matrix components, such as type 1 collagen. More recently, fibronectin was shown to stimulate the phosphatidylinositol 3-kinase (PI3K), which is capable of controlling the expression of cyclin D and related genes involved in cell cycle control (9,10). The above information suggests that fibronectin promotes lung tumor growth/survival and resistance to therapy and could represent a novel target for the development of new anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Fibronectin Stimulates Non–Small Cell Lung Carcinoma Cell Growth through Activation of Akt/Mammalian Target of Rapamycin/S6 Kinase and Inactivation of LKB1/AMP-Activated Protein Kinase Signal Pathways

2006

View full text Add to dashboard Cite

The Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathway is considered a central regulator of protein synthesis and of cell proliferation, differentiation, and survival. However, the role of the Akt/mTOR/ p70S6K pathway in lung carcinoma remains unknown. We previously showed that fibronectin, a matrix glycoprotein highly expressed in tobacco-related lung disease, stimulates non-small cell lung carcinoma (NSCLC) cell growth and survival. Herein, we explore the role of the Akt/mTOR/p70S6K pathway in fibronectin-induced NSCLC cell growth. We found that fibronectin stimulated the phosphorylation of Akt, an upstream inducer of mTOR, and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), two downstream targets of mTOR in NSCLC cells (H1792 and H1838), whereas it inhibited the phosphatase and tensin homologue deleted on chromosome 10, a tumor suppressor protein that antagonizes the phosphatidylinositol 3-kinase/Akt signal. In addition, treatment with fibronectin inhibited the mRNA and protein expression of LKB1 as well as the phosphorylation of AMP-activated protein kinase (AMPKA), both known to down-regulate mTOR. Rapamycin, an inhibitor of mTOR, blocked the fibronectin-induced phosphorylation of p70S6K and 4E-BP1. Akt small interfering RNA (siRNA) and an antibody against the fibronectin-binding integrin A 5 B 1 also blocked the p70S6K phosphorylation in response to fibronectin. In contrast, an inhibitor of extracellular signal-regulated kinase 1/2 (PD98095) had no effect on fibronectin-induced phosphorylation of p70S6K. Moreover, the combination of rapamycin and siRNA for Akt blocked fibronectin-induced cell proliferation. Taken together, these observations suggest that fibronectininduced stimulation of NSCLC cell proliferation requires activation of the Akt/mTOR/p70S6K pathway and is associated with inhibition of LKB1/AMPK signaling. (Cancer Res 2006; 66(1): 315-23)

show abstract

Extracellular matrix-dependent myosin dynamics during G1-S phase cell cycle progression in hepatocytes

Cited by 18 publications

References 79 publications

An MLCK-dependent window in late G1 controls S phase entry of proliferating rodent hepatocytes via ERK-p70S6K pathway

An MLCK-dependent window in late G1 controls S phase entry of proliferating rodent hepatocytes via ERK-p70S6K pathway

Regulation of the G1/S Transition in Adult Liver: Expression and Activation of the Cyclin Dependent Kinase Cdk1 in Differentiated Hepatocytes is Controlled by Extracellular Signals and is Crucial for Commitment to DNA Replication

Fibronectin Stimulates Non–Small Cell Lung Carcinoma Cell Growth through Activation of Akt/Mammalian Target of Rapamycin/S6 Kinase and Inactivation of LKB1/AMP-Activated Protein Kinase Signal Pathways

Contact Info

Product

Resources

About