PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt
ABSTRACT p53 And Akt are critical players regulating tumorigenesis with opposite effects: whereas p53 transactivates target genes to exert its function as a tumor suppressor, Akt phosphorylates its substrates and transduces downstream survival signals. In addition, p53 and Akt negatively regulate each other to balance survival and death signals within a cell. We now identify PHLDA3 as a p53 target gene that encodes a PH domain-only protein. We find that PHLDA3 competes with the PH domain of Akt for binding of membrane lipids, thereby inhibiting Akt translocation to the cellular membrane and activation. Ablation of endogenous PHLDA3 results in enhanced Akt activity and decrease of p53-dependent apoptosis. We also demonstrate the suppression of anchorage-independent cell growth by PHLDA3. Loss of the PHLDA3 genomic locus was frequently observed in primary lung cancers, suggesting a role of PHLDA3 in tumor suppression. Our results reveal a new mode of coordination between the p53 and Akt pathways.
Full-textDOI: · Available from: Fumio Tashiro, Mar 13, 2014
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- "Then, we focused on a strongly regulated novel gene, PHLDA1 as it has not been investigated before as a target of oncogenic pathways. This gene shares a pleckstrin-homology (PH) domain with PHLDA3, which was shown to be a direct target gene of p53 and functions as a unique AKT inhibitor through the depletion of membrane-bound phosphatidyl inositols , . The exact functions of PHLDA1 are poorly defined. "
ABSTRACT: We set out to study the key effectors of resistance and sensitivity to ErbB2 tyrosine kinase inhibitors, such as lapatinib in ErbB2-positive breast and lung cancers. A cell-based in vitro site-directed mutagenesis lapatinib resistance model identified several mutations, including the gatekeeper ErbB2 mutation ErbB2-T798I, as mediating resistance. ErbB2-T798I engineered cell models indeed show resistance to lapatinib but remain sensitive to the irreversible EGFR/ErbB2 inhibitor, PD168393, suggestive of potential alternative treatment strategies to overcome resistance. Gene expression profiling studies identified a select group of downstream targets regulated by ErbB2 signaling and define PHLDA1 as an immediately downregulated gene upon oncogenic ErbB2 signaling inhibition. We find significant down-regulation of PHLDA1 in primary breast cancer and PHLDA1 is statistically significantly less expressed in ErbB2 negative compared with ErbB2 positive tumors consistent with its regulation by ErbB2. Lastly, PHLDA1 overexpression blocks AKT signaling, inhibits cell growth and enhances lapatinib sensitivity further supporting an important negative growth regulator function. Our findings suggest that PHLDA1 might have key inhibitory functions in ErbB2 driven lung and breast cancer cells and a better understanding of its functions might point at novel therapeutic options. In summary, our studies define novel ways of modulating sensitivity and resistance to ErbB2 inhibition in ErbB2-dependent cancers.PLoS ONE 09/2014; 9(9):e106349. DOI:10.1371/journal.pone.0106349 · 3.23 Impact Factor
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- "Conversely, phosphorylation of Akt was increased by knockdown of p53 in human endothelial cells (Figure S4A). We also found that the expression of phosphatase and tensin homolog (PTEN) and pleckstrin homology-like domain, family A, member 3 (PHLDA3) was positively regulated by p53 (Figures 4B, S4A, and S4B), both of which are known to be target genes of p53 that inhibit Akt phosphorylation in cancer cells (Cantley and Neel, 1999; Kawase et al., 2009; Stambolic et al., 2001). Accordingly , we examined the effect of deletion of these genes on eNOS phosphorylation in endothelial cells. "
ABSTRACT: Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.046 · 8.36 Impact Factor
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- "Typically proteins with PH domains are active in intracellular trafficking, cell signalling and membrane-cytoskeletal interactions. Co-expression and homology of PHLDA2 to TDAG51 (which induces Fas expression and Fas-mediated apoptosis) and the role of the closely related Phlda3 gene in inhibiting Akt -regulated processes  also suggests a role for PHLDA2 in apoptosis or growth suppression, although this has not been demonstrated experimentally. PHLDA2 is expressed monoallelically from the maternal allele in the human placenta   and human fetal tissues including the kidney, intestine, limb, liver and lung . "
ABSTRACT: In utero growth restriction is the failure of a fetus to achieve its genetic growth potential during gestation. Elevated expression of the maternally expressed imprinted gene PHLDA2, has been reported in the human placenta of growth restricted pregnancies. A mouse modelling this alteration has been generated and also displays fetal growth restriction suggesting that increased expression of PHLDA2 is not an effect but rather a cause of growth restriction in human pregnancies. Here we review the current data linking PHLDA2 to growth restriction and the data from human and animal model studies suggesting that placental PHLDA2 expression may be responsive to environmental stimuli such as maternal lifestyle. Further investigation is warranted in larger studies of human placentas with the aim of determining whether placental PHLDA2 expression could be used as a diagnostic tool to identify or sub-classify growth restricted infants and to inform more effective interventions and treatment for IUGR in the future.Placenta 05/2014; 35(8). DOI:10.1016/j.placenta.2014.04.018 · 3.29 Impact Factor