RasGRP1 Represents a Novel Non-protein Kinase C Phorbol Ester Signaling Pathway in Mouse Epidermal Keratinocytes

Rambaratsingh, Reshmi A.; Stone, James C.; Blumberg, Peter M.; Lorenzo, Patricia S.

doi:10.1074/jbc.m308240200

Cited by 40 publications

(54 citation statements)

References 39 publications

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“…Similarly, 10 Amol/L GF109203X did not have any effect on Ras activation induced by 5-minute treatment with 1 Amol/L TPA. Nevertheless, as we have reported previously for TPA (10), acute activation of extracellular signal-regulated kinase (ERK) by bryostatin 1 was sensitive to PKC inhibition (data not shown).…”

Section: Bryostatin 1 Is Less Effective Than Tpa At Inducing Ras Actimentioning

confidence: 70%

“…We have recently shown that the novel DAG receptor and Ras exchange factor RasGRP1 is expressed in mouse epidermal keratinocytes and mediates activation of Ras by TPA in a PKC-independent manner (10). The purpose of the work described here was to determine if bryostatin 1 could also modulate RasGRP1 in the mouse keratinocyte system and to compare its effects with those of TPA.…”

Section: Introductionmentioning

confidence: 99%

“…We have shown previously that in mouse keratinocytes TPA treatment recruits RasGRP1 to the plasma membrane (10). To examine the ability of bryostatin 1 to cause RasGRP1 translocation, we expressed a GFP-tagged version of RasGRP1 (RasGRP1-GFP) in the keratinocyte cell line SP-1 and followed the subcellular distribution by livecell confocal microscopy.…”

Section: Bryostatin 1 and Tpa Induce Different Patterns Of Rasgrp1 Trmentioning

confidence: 99%

“…Previously, we showed that TPA is able to down-regulate RasGRP1 in primary mouse keratinocytes (10). To analyze if the effect of bryostatin 1 differed from that of TPA on RasGRP1 degradation, we treated primary cells with increasing concentrations of bryostatin 1 for 24 hours and then measured the levels of RasGRP1 in whole-cell lysates.…”

Section: Bryostatin 1 Is Less Effective Than Tpa At Inducing Ras Actimentioning

confidence: 99%

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Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes

Tuthill

Oki

Lorenzo

2006

Molecular Cancer Therapeutics

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The antitumor agent bryostatin 1 and the tumorpromoting phorbol esters function as structural mimetics of the second lipid messenger diacylglycerol (DAG) by binding to the C1 domain of DAG receptors. However, bryostatin 1 and the phorbol esters often differ in their cellular actions. In mouse skin, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter, whereas bryostatin 1 lacks this activity and antagonizes the tumor-promoting effects of TPA. Although protein kinase C mediates many of the effects of DAG on skin, the exact mechanisms responsible for the biology of bryostatin 1 and TPA in the epidermis have not been elucidated. We recently reported that the novel DAG receptor RasGRP1 is expressed in mouse keratinocytes and mediates TPA-induced Ras activation. This finding prompted us to examine the regulation of RasGRP1 by bryostatin 1. We found that whereas TPA induced translocation of RasGRP1 to both the plasma and internal membranes of the keratinocytes, bryostatin 1 recruited RasGRP1 only to internal membranes and the nuclear envelope. In addition, TPA led to a concentration-dependent down-regulation of RasGRP1, whereas bryostatin 1 failed to induce full RasGRP1 downregulation. Interestingly, bryostatin 1 was less effective than TPA at activating Ras. The results presented here suggest the possibility that a differential modulation of RasGRP1 by bryostatin 1 compared with TPA could participate in the disparate responses of the epidermal cells to both DAG analogues. This result may have implications in the understanding of the antitumor effects of bryostatin 1 in the skin. [Mol Cancer Ther 2006;5(3):602 -10]

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Section: Bryostatin 1 Is Less Effective Than Tpa At Inducing Ras Actimentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Bryostatin 1 and Tpa Induce Different Patterns Of Rasgrp1 Trmentioning

confidence: 99%

Section: Bryostatin 1 Is Less Effective Than Tpa At Inducing Ras Actimentioning

confidence: 99%

See 2 more Smart Citations

Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes

Tuthill

Oki

Lorenzo

2006

Molecular Cancer Therapeutics

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“…This suggests the possible involvement of a calciumdependent Rac/Cdc42 GEF. Although calcium-regulated GEF for Ras, R-Ras and Rap-1 have been identified [49,50], a calcium-dependent Rac/Cdc42-GEF has not yet been described. Alternatively, the calcium-dependent phosphorylation of RhoGDIa leads to Rac membrane translocation and activation in PC3 human prostrate cells [51].…”

Section: Discussionmentioning

confidence: 99%

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

El‐Sibai

Backer

2006

Eur J Immunol

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The Rho GTPases Rac and Cdc42 play a central role in the regulation of secretory and cytoskeletal responses in antigen-stimulated mast cells. In this study, we examine the kinetics and mechanism of Rac and Cdc42 activation in the rat basophilic leukemia RBL-2H3 cells. The activation kinetics of both Rac and Cdc42 show a biphasic profile, consisting of an early transient peak at 1 min and a late sustained activation phase at 20-40 min. The inhibition of phospholipase C (PLC)c causes a twofold increase in Rac and Cdc42 activation that coincides with a dramatic production of atypical filopodialike structures. Inhibition of protein kinase C using bisindolylmaleimide mimics the effect of PLCc inhibition on Rac activation, but not on Cdc42 activation. In contrast, depletion of intracellular calcium leads to a complete inhibition of the early activation peak of both Rac and Cdc42, without significant effects on the late sustained activation. These data suggest that PLCc is involved in a negative feedback loop that leads to the inhibition of Rac and Cdc42. They also suggest that the presence of intracellular calcium is a prerequisite for both Rac and Cdc42 activation. IntroductionMast cells participate in the pathogenesis of immediate hypersensitivity and allergic reactions in humans [1]. Moreover, mast cells are important contributors to airway hyper-responsiveness that occurs in asthmatic inflammation [2]. In response to allergens and other exogenous stimuli, mast cells accumulate in the airway smooth muscle and in the bronchial intraepithelial layer [3]. The activation of mast cells, through the crosslinking of the FceRI, leads to the release of pre-formed early-phase inflammatory mediators and vasoactive substances from granules. It also leads to the in situ production of cytokines and bioactive lipids that contribute to the late-phase manifestation of the asthmatic reaction [4].Aggregation of FceRI on the surface of mast cells in response to multivalent ligand binding initiates a cascade of downstream signaling effectors that leads to degranulation [5]. These include phosphatidylinositol 3-kinase (PI3K), the guanine nucleotide exchange factor Vav, and phospholipase C (PLC)c1 [6]. The early activation of PLCc1 results in the generation of inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. These two second messengers lead to increases in cytoplasmic calcium and activation of calcium/diacylglycerol-regulated isoforms of protein kinase C (PKC) which culminate in granule margination and exocytosis [7]. PI3K plays an important regulatory role as an upstream activator of PLCc1, as well as a regulator of calcium flux during mast cell degranulation [8][9][10][11][12][13].Members of the Rho family of small GTPases also regulate signaling events in mast cells [14][15][16]. In the rat basophilic leukemia (RBL-2H3) cells, Rac and Cdc42 have been implicated in the control of the FceRImediated phagocytosis and the regulation of migration, In conjunction with the secretory response, antigenstimulated mast cells undergo drama...

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Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes

Perez

Yang

Campain

2007

J of Applied Toxicology

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Both arsenic and benzo[a]pyrene (BaP) inhibit terminal differentiation and alter growth potential in normal human epidermal keratinocytes (NHEK) in vitro. To identify molecular alterations that may be involved in these cellular processes, microarray analysis was carried out on NHEK treated with BaP or arsenic. The gene expression microarray results measuring mRNA levels were as follows: (1) in total, the expression of 85 genes was induced and 17 genes was suppressed by 2.0 microm BaP. (2) Arsenic at an equitoxic dose (5.0 microm) induced the expression of 106 and suppressed 15 genes. Quantitative real-time RT-PCR was used subsequently to confirm microarray findings on selected genes involved in keratinocyte growth and differentiation pathways. These studies confirmed increased mRNA levels in NHEK by BaP of alpha-integrin binding protein 63 (AIBP63) (2.48-fold), retinoic acid- and interferon-inducible protein (IFIT5) (2.74-fold), interleukin-1 alpha (IL1A) (2.64-fold), interleukin-1 beta (IL1B) (2.84-fold) and Ras guanyl releasing protein 1 (RASGRP1) (3.14-fold). Real-time RT-PCR confirmed that arsenic increased mRNA levels of the following genes: retinoblastoma 1 (RB1) (5.4-fold), retinoblastoma-binding protein 1 (ARID4A) (6.8-fold), transforming growth factor beta-stimulated protein (TSC22D1) (6.84-fold), MAX binding protein (MNT) (2.44-fold), and RAD50 (4.24-fold). Collectively, these results indicate that these chemicals target different genes and molecular pathways involved in the regulatory processes controlling NHEK proliferation and differentiation. Mechanistic studies with a subset of genes may allow the correlation of alterations in these molecular markers with chemical-specific blocks to differentiation in NHEK.

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RasGRP1 Represents a Novel Non-protein Kinase C Phorbol Ester Signaling Pathway in Mouse Epidermal Keratinocytes

Cited by 40 publications

References 39 publications

Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes

Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes

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