Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase

Bi, Lei; Okabe, Ichiro; Bernard, David; Nussbaum, Robert L.

doi:10.1007/s00335-001-2123-x

Cited by 119 publications

(97 citation statements)

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“…In contrast to p110a and p110b whose genetic inactivation in mice leads to an early embryonic lethality [36,37], p110c and p110d knockout mice are viable but show defective immune responses [38,39]. Thus, p110c and p110d have been identified as PI3K signaling mediators in the immune system.…”

Section: Discussionmentioning

confidence: 79%

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

Cui

Yang

2011

Cell Biochem Biophys

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The phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway plays a critical role in human cancer. We determined the expression patterns of class I PI3K catalytic subunits and evaluated their importance in the development or progression of colorectal cancer (CRC). For this purpose, expression of class I PI3K isoforms was evaluated in 82 primary CRC and paired non-cancerous mucosa samples by qRT-PCR. P-AKT-Ser473 and P-AKT-Thr308 expression were measured by western blot. We found that, compared with paired non-cancerous mucosa samples, mRNA expression of p110α and p110β in CRCs was significantly increased to 2.02-fold (95% confidence interval [CI] 1.25-3.28 fold) and 1.76-fold (95% CI 1.19-2.60 fold), respectively; while slight differences were found regarding the expression of p110δ (0.57-fold; 95% CI 0.31-1.07 fold) and p110γ (0.97-fold; 95% CI 0.50-1.88 fold). Increased p110α and p110β expression correlated with primary tumor size, regional lymph node metastases, and AJCC stage. Increased p110β expression also correlated with distant metastasis. P-AKT-Thr308 and P-AKT-Ser473 expression showed significant direct correlations with p110α and p110β mRNA expression. Besides, CRC patients with p110β mRNA overexpression had a worse disease-free survival after radical surgery compared with those with normal or decreased levels (P = 0.043). It was, therefore, concluded that the altered p110α and p110β expression might contribute to the CRC development or progression.

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Section: Discussionmentioning

confidence: 79%

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

Cui

Yang

2011

Cell Biochem Biophys

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“…To date, there have been no reports of viable mice expressing mutant or deletion forms of p110α or p110β, suggesting an indispensable role for these enzymes in normal mouse development [8,9]. To investigate the role of p110β in platelets, we have recently developed isoform-selective inhibitors that have approximately 100-1000 fold selectivity for p110β over p110α and p110γ, and 20-100-fold selectivity over p110δ [36].…”

Section: Importance Of Type I Pi3k In Platelets Type Ia Pi3ksmentioning

confidence: 98%

Type I phosphoinositide 3-kinases: potential antithrombotic targets?

Jackson

Schoenwaelder

2006

Cell. Mol. Life Sci.

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Arterial thrombosis is the single most common cause of death and disability in industrialized societies and is the primary pathogenic mechanism underlying acute myocardial infarction and ischemic stroke. Platelets play a central role in this process, and as a consequence, a great deal of effort has gone into identifying the mechanisms regulating the adhesive function of platelets. Platelet adhesion is controlled by intracellular signaling pathways, with growing evidence for a major role for phosphoinositide 3-kinases (PI3Ks) in this process. Platelets express all type I PI3K isoforms, including p110alpha, p110beta, p110delta and p110gamma, with recent evidence suggesting important roles for p110gamma and p110beta in regulating distinct phases of the platelet activation process. Deficiency of p110 gamma or inhibition of p110beta produces a marked defect in arterial thrombosis without a corresponding increase in bleeding time, raising the possibility that inhibition of one or more PI3K isoforms may represent an effective antithrombotic approach.

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“…Elucidating the role of the ubiquitously expressed p110a and p110b in T cell function has been hampered by the embryonic lethality of mice deficient for these isoforms [55,56]. In these conditions, the interest has focused on the role in thymus cell differentiation, T cell activation, differentiation and trafficking, or the impact in autoimmune diseases of the class IA p110d and class IB p110c catalytic subunits, whose expression is particularly high in leukocytes (reviewed in [22][23][24]).…”

Section: Pi3-kinase Subunits In Phosphorylated Icos and In Immunoprecmentioning

confidence: 99%

Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278)

Acosta

Zafra

Ojeda

et al. 2010

Cell. Mol. Life Sci.

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To better understand T lymphocyte costimulation by inducible costimulator (ICOS; H4; CD278), we analyzed proteins binding to ICOS peptides phosphorylated at the Y(191)MFM motif. Phosphorylated ICOS binds class IA phosphatidyl inositol 3-kinase (PI3-K) p85α, p50-55α and p85β regulatory subunits and p110α, p110δ and p110β catalytic subunits. Intriguingly, T cells expressed high levels of both p110α or p110δ catalytic subunits, yet ICOS peptides, cell surface ICOS or PI3-kinase class IA regulatory subunits preferentially coprecipitated p110α catalytic subunits. Silencing p110α or p110δ partially inhibited Akt/PKB activation induced by anti-CD3 plus anti-ICOS antibodies. However, silencing p110α enhanced and silencing p110δ inhibited Erk activation. Both p110α- and p110δ-specific inhibitors blocked cytokine secretion induced by TCR/CD3 activation with or without ICOS costimulus, but only p110α inhibitors blocked ICOS-induced cell elongation. Thus, p110α and p110δ are essential to optimal T cell activation, but their abundance and activity differentially tune up distinct ICOS signaling pathways.

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Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase

Cited by 119 publications

References 0 publications

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

Type I phosphoinositide 3-kinases: potential antithrombotic targets?

Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278)

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