Loss of Cbl-PI3K Interaction Enhances Osteoclast Survival due to p21-Ras Mediated PI3K Activation Independent of Cbl-b

AbstractInflammation is a natural defense process of the innate immune system, associated with the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-12 and TNFα; and enzymes including iNOS through the activation and nuclear translocation of NF-κB p65 due to the phosphorylation of IκBα. Regulation of intracellular Ca2+ is considered a promising strategy for the prevention of reactive oxygen species (ROS) production and accumulation of DNA double strand breaks (DSBs) that occurs in inflammatory-associated-diseases. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A (UA) has received an increasing attention as a novel candidate with anti-inflammatory and anti-oxidant effects. Here, we investigated the effect of UA on the suppression of pro-inflammatory molecules and NF-κB activation by targeting TLR4 signalling pathway. We also identified the influence of UA on Ca2+ entry, ROS production and DSBs availability in murine bone-marrow-derived macrophages challenged with lipopolysaccharides (LPS). We found that UA inhibits IκBα phosphorylation and supresses MAPK and PI3K activation. In addition, UA was able to reduce calcium entry, ROS production and DSBs availability. In conclusion, we suggest that urolithin A is a promising therapeutic agent for treating inflammatory diseases through suppression of NF-κB and preserving DNA through maintaining intracellular calcium and ROS homeostasis.

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Protein kinase A and protein kinase Cα/PPP1CC2 play opposing roles in the regulation of phosphatidylinositol 3-kinase activation in bovine sperm

Reproduction ◽

10.1530/rep-09-0314 ◽

2010 ◽

Vol 140 (1) ◽

pp. 43-56 ◽

Cited By ~ 16

Author(s):

T Rotman ◽

N Etkovitz ◽

A Spiegel ◽

S Rubinstein ◽

H Breitbart

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Reproductive Tract ◽

Female Reproductive Tract ◽

Phosphatidylinositol 3 Kinase ◽

Highly Active ◽

Protein Kinase Cα ◽

Pi3k Activation ◽

Kinase A ◽

Phosphatidylinositol 3

In order to acquire fertilization competence, spermatozoa have to undergo biochemical changes in the female reproductive tract, known as capacitation. Signaling pathways that take place during the capacitation process are much investigated issue. However, the role and regulation of phosphatidylinositol 3-kinase (PI3K) in this process are still not clear. Previously, we reported that short-time activation of protein kinase A (PRKA, PKA) leads to PI3K activation and protein kinase Cα (PRKCA, PKCα) inhibition. In the present study, we found that during the capacitation PI3K phosphorylation/activation increases. PI3K activation was PRKA dependent, and down-regulated by PRKCA. PRKCA is found to be highly active at the beginning of the capacitation, conditions in which PI3K is not active. Moreover, inhibition of PRKCA causes significant activation of PI3K. Similar activation of PI3K is seen when the phosphatase PPP1 is blocked suggesting that PPP1 regulates PI3K activity. We found that during the capacitation PRKCA and PPP1CC2 (PP1γ2) form a complex, and the two enzymes were degraded during the capacitation, suggesting that this degradation enables the activation of PI3K. This degradation is mediated by PRKA, indicating that in addition to the direct activation of PI3K by PRKA, this kinase can enhance PI3K phosphorylation indirectly by enhancing the degradation and inactivation of PRKCA and PPP1CC2.

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Mouse cells contain two distinct ras gene mRNA species that can be translated into a p21 onc protein

Molecular and Cellular Biology ◽

10.1128/mcb.2.11.1339-1345.1982 ◽

1982 ◽

Vol 2 (11) ◽

pp. 1339-1345

Author(s):

R W Ellis ◽

D DeFeo ◽

M E Furth ◽

E M Scolnick

Keyword(s):

Normal Mouse ◽

Velocity Sedimentation ◽

Ras Gene ◽

Mrna Species ◽

P21 Ras ◽

Murine Sarcoma Virus ◽

Sarcoma Virus ◽

Mouse Cells ◽

Murine Sarcoma

The Kirsten (Ki) and Harvey (Ha) strains of murine sarcoma virus encode a 21,000-dalton protein (p21 ras) which is the product of the transforming gene of these viruses. Normal cells express low levels of p21 ras encoded by cellular genes (Ki-ras and Ha-ras) homologous to the Ki and Ha murine sarcoma virus transformation genes. A bone marrow-derived mouse cell line, 416B, has been shown to express unusually high levels of p21 ras. In this manuscript, we investigated the molecular biology of p21 ras gene expression in 416B and other normal mouse cells. We identified four distinct polyadenylated and polysome-associated RNAs, two related to Ki-ras and two to Ha-ras. The levels in 416B cells of the two Ki-ras RNAs, sized 5.2 and 2.0 kilobases, were both elevated approximately 25-fold over levels found in normal mouse cells; there was no corresponding change in 416B cells in the levels of the two Ha-ras RNAs. We partially purified the two Ki-ras mRNAs and separated them by velocity sedimentation in sucrose density gradients. Both the 5.2- and 2.0-kilobase mRNAs could be translated in vitro into p21 ras. These results show that a cellular onc protein can be translated from two distinct cellular mRNA species.

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The mRNA 5' cap-binding protein, eIF-4E, cooperates with v-myc or E1A in the transformation of primary rodent fibroblasts

Molecular and Cellular Biology ◽

10.1128/mcb.12.3.1234-1238.1992 ◽

1992 ◽

Vol 12 (3) ◽

pp. 1234-1238

Author(s):

A Lazaris-Karatzas ◽

N Sonenberg

Keyword(s):

Signal Transduction ◽

Binding Protein ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Rat Embryo ◽

Present Evidence ◽

P21 Ras ◽

Embryo Fibroblasts ◽

Common Signal

We present evidence that eIF-4E, the mRNA 5' cap-binding protein, cooperates with two immortalizing oncogenes, v-myc and E1A, to cause transformation of rat embryo fibroblasts. eIF-4E alone can transform rat embryo fibroblasts when selection is applied. The pattern of transformation by eIF-4E is similar to that of p21 Ras, raising the possibility that eIF-4E shares a common signal transduction pathway with p21 Ras.

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Tumours with PI3K activation are resistant to dietary restriction

Nature ◽

10.1038/nature07782 ◽

2009 ◽

Vol 458 (7239) ◽

pp. 725-731 ◽

Cited By ~ 300

Author(s):

Nada Y. Kalaany ◽

David M. Sabatini

Keyword(s):

Dietary Restriction ◽

Pi3k Activation

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Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

Blood ◽

10.1182/blood-2018-06-856203 ◽

2018 ◽

Vol 132 (25) ◽

pp. 2670-2683 ◽

Cited By ~ 15

Author(s):

Eleni Kabrani ◽

Van Trung Chu ◽

Evangelia Tasouri ◽

Thomas Sommermann ◽

Kevin Baßler ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Transcriptional Activity ◽

Tumor Development ◽

Pi3k Pathway ◽

Forkhead Box ◽

Nuclear Exclusion ◽

Pi3k Activation ◽

Phosphoinositide 3 Kinase ◽

Human And Mouse

Abstract Forkhead box class O1 (FOXO1) acts as a tumor suppressor in solid tumors. The oncogenic phosphoinositide-3-kinase (PI3K) pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B-cell–derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations, which prevent AKT targeting and lock the transcription factor in the nucleus, are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell–derived lymphomagenesis.

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