The Ras/Rac1/Cdc42/SEK/JNK/c-Jun Cascade Is a Key Pathway by Which Agonists Stimulate DNA Synthesis in Primary Cultures of Rat Hepatocytes

Auer, Kelly L.; Contessa, Joseph N.; Brenz-Verca, Stefano; Pirola, Luciano; Rusconi, Sandro; Cooper, Geoffrey M.; Abo, Arie; Wymann, Matthias P.; Davis, Roger J.; Birrer, Michael J.; Dent, Paul

doi:10.1091/mbc.9.3.561

Cited by 126 publications

(120 citation statements)

References 57 publications

(68 reference statements)

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“…Although dominant-negative PI3K did not inhibit DNA synthesis in hepatocytes, other data suggested that the cascade inhibition could abolish or only delay entry to S phase. 17,19,37 Our study clearly shows that the PI3K inhibitor, LY294002, and the FRAP/mTOR inhibitor, rapamycin, do not delay entry to S phase and expression of cyclin D1 but totally abolish DNA replication and the cyclin induction in growth factor-stimulated hepatocytes. Uncoupling of mRNA and protein levels has been pointed out in hepatocytes, suggesting that cyclin D1 is subject to control on a translation level and/or protein stability in rat liver.…”

Section: Discussionmentioning

confidence: 66%

“…Concerning PI3K, few studies have been performed on hepatocytes, and those studies had conflicting results. [17][18][19][20] In this report, we analyzed the possible role of the PI3K pathway in the regulation of EGF-induced DNA replication and survival in mid-late G1 phase. We examined the relation that could exist between this pathway and the expression of cyclin D1, a critical player in G1/S transition, and questioned the interference that could exist between the PI3K and MEK/ERK pathways.…”

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confidence: 99%

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PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival

Coutant¹,

Rescan²,

Gilot³

et al. 2002

Hepatology

119

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Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication. (HEPATOLOGY 2002;36:1079-1088 C ell cycle progression through G1 phase requires the integration of signals from the extracellular environment such as growth factors, cytokines, and extracellular matrix proteins mediated by different transduction cascades. The ability to induce cellular proliferation is often correlated with the ability to promote cell survival. Two signaling cascades have emerged as major players in the mitogenic and antiapoptotic response in many cells: the mitogen-activated protein kinase (MEK)/ extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K) pathways.Growth factors as survival factors bind to cell surface receptors and trigger the activation of several kinases, including PI3K, which seems to be implicated in the control of growth and apoptosis of a wide range of cell types. 1 This kinase activates PDK1 that in turn leads to the activation of a serine/threonine kinase termed AKT or PKB, which plays a central role in promoting the survival of many cell types. PDK1 also phosphorylates and activates FRAP/mTOR (target of rapamycin). p70s6k, which regulates the ribosomal S6 subunit phosphorylation in response to mitogens, is controlled by FRAP/mTOR and plays an essential role in the translation machinery. 2-4 FRAP/mTOR also controls the phosphorylation of 4E-BP1, a key protein involved in t...

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival

Coutant¹,

Rescan²,

Gilot³

et al. 2002

Hepatology

119

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“…41 The finding that mrp1 induction in cultured hepatocytes takes place at the mid G 1 -phase of the cell cycle 42 further supports our finding, because cytokines such as TNF-␣ and interleukin-6 are known to initiate a proliferation trigger in hepatocytes in vivo. [43][44][45][46] We hypothesize that ABC-transporters like MDR1 and MRP1 and their rodent homologues function as an aspecific protection system to maintain cellular membrane integrity by extruding cytotoxic compounds such as lipid peroxidation products. Furthermore, MRP1/mrp1 may contribute to the regulation of the intracellular redox state by transporting glutathione disulfide.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of the multidrug resistance genes,Mrp1andMdr1b, and down-regulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver

Vos¹,

Hooiveld²,

Koning³

et al. 1998

Hepatology

333

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Endotoxin-induced cholestasis is mainly caused by an impaired canalicular secretion. Mrp2, the canalicular multispecific organic anion transporter, is strongly downregulated in this situation, and canalicular bile salt secretion is also reduced. We hypothesized that other adenosine triphosphate-binding cassette (ABC) transporters may compensate for the decreased transport activity to protect the cell from cytokine-induced oxidative damage. Therefore, we examined the expression of ABC-transport proteins in membrane fractions of whole liver and of isolated hepatocytes of endotoxin-treated rats and performed reversetranscriptase polymerase chain reaction (RT-PCR) on mRNA isolated from these livers. In addition, the localization of these transporters was examined using confocal scanning laser microscopy. By 6 hours after endotoxin administration, we found a clear increase of mrp1 mRNA and protein, whereas mrp2 mRNA and protein were decreased. This was confirmed in isolated hepatocytes. In addition, mdr1b mRNA was strongly increased, whereas mdr1a and mdr2 mRNA did not change significantly. Both the mRNA and protein levels of the sister of P-glycoprotein (spgp), the recently cloned bile salt transporter, decreased. After endotoxin treatment, the normally sharply delineated canalicular staining of mrp2 and spgp had changed to a fuzzy pattern, suggesting localization in a subapical compartment. We conclude that endotoxin-induced cholestasis is caused by decreased mrp2 and spgp levels, as well as an abnormal localization of these proteins. The simultaneous up-regulation of mrp1 and mdr1b may confer resistance to hepatocytes against cytokine-induced metabolic stress. (HEPATOLOGY 1998;28:1637-1644.)Excretion of a large variety of endogenous and exogenous compounds from hepatocytes into bile is an adenosine triphosphate (ATP)-dependent process, predominantly performed by members of the P-glycoprotein (Pgp) subfamily and the multidrug-resistance protein (MRP) subfamily of the ATP-binding cassette (ABC) protein superfamily. 1,2 At least four members of the Pgp subfamily are located at the canalicular membrane of rodent liver: mdr1a, mdr1b, mdr2, and spgp. In normal rodent liver, mdr1a and mdr1b are present at low levels. Overexpression of mouse mdr1a/mdr1b confers multidrug resistance against a broad variety of natural product drugs. 3,4 The main physiological function of these multidrug-resistance proteins is presumably the transport of bulky amphiphilic compounds, such as cationic drugs, hydrophobic peptides, steroids, and atypical glycolipids, across the canalicular membrane. 1,4,5 The expression of mdr2 in normal rodent liver is high. This transporter functions as a flippase that translocates phosphatidylcholine across the membrane. 6 From pig liver, Childs et al. cloned part of another member of the Pgp subfamily: the sister gene of Pgp (spgp). 7 Most recently, Gerloff et al. cloned the full-length cDNA of spgp from rat liver. 8 They provided evidence that spgp, which is exclusively present in the liver, most likely is ...

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“…Activation of SEK results in the phosphorylation and activation of JNK (Sanchez et al, 1994;Auer et al, 1998;Wang et al, 1999a). The effect of UV irradiation-induced hyperactivity of K + channel on SEK activation is observed by measuring the phosphorylation status of SEK.…”

Section: Uv Irradiation-induced K + Channel and Sek Activationmentioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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The Ras/Rac1/Cdc42/SEK/JNK/c-Jun Cascade Is a Key Pathway by Which Agonists Stimulate DNA Synthesis in Primary Cultures of Rat Hepatocytes

Cited by 126 publications

References 57 publications

PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival

PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival

Up-regulation of the multidrug resistance genes,Mrp1andMdr1b, and down-regulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

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