PH Domain And Leucine Rich Repeat Protein Phosphatase 1 Research Articles

MicroRNA-299a-5p Protects against Spinal Cord Injury through Activating AMPK Pathway.

Objective Inflammation and oxidative stress are implicated in the pathogenesis of spinal cord injury (SCI). The present study is aimed at investigating the function and molecular basis of microRNA-299a-5p (miR-299a-5p) during SCI in mice. Methods Mice were exposed to SCI surgery and then intrathecally injected with the agomir, antagomir, or matched negative controls of miR-299a-5p to overexpress or silence miR-299a-5p. To inhibit AMP-activated protein kinase (AMPK), mice were intraperitoneally injected with compound C (CC). To overexpress pH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), lentiviral vectors were used. Results The miR-299a-5p expression in the spinal cord was dramatically reduced by SCI stimulation. The miR-299a-5p agomir prevents, while the miR-299a-5p antagomir exacerbates inflammation, oxidative stress, and SCI in mice. Mechanistically, we found that miR-299a-5p directly inhibited PHLPP1 and subsequently activated AMPK pathway. The PHLPP1 overexpression of AMPK inhibition with either genetic or pharmacologic methods dramatically abolished the miR-299a-5p agomir-mediated protective effects against SCI. Conclusion miR-299a-5p protects against spinal cord injury through activating AMPK pathway.

Leptin Modulates the Metastasis of Canine Inflammatory Mammary Adenocarcinoma Cells Through Downregulation of Lysosomal Protective Protein Cathepsin A (CTSA).

Canine malignant mammary gland tumors present with a poor prognosis due to metastasis to other organs, such as lung and lymph node metastases. Unlike in human studies where obesity has been shown to increase the risk of breast cancer, this has not been well studied in veterinary science. In our preliminary study, we discovered that leptin downregulated cathepsin A, which is responsible for lysosomal-associated membrane protein 2a (LAMP2a) degradation. LAMP2a is a rate-limiting factor in chaperone-mediated autophagy and is highly active in malignant cancers. Therefore, in this study, alterations in metastatic capacity through cathepsin A by leptin, which are secreted at high levels in the blood of obese patients, were investigated. We used a canine inflammatory mammary gland adenocarcinoma (CHMp) cell line cultured with RPMI-1640 and 10% fetal bovine serum. The samples were then subjected to real-time polymerase chain reaction, Western blot, immunocytochemistry, and lysosome isolation to investigate and visualize the metastasis and chaperone-mediated autophagy-related proteins. Results showed that leptin downregulated cathepsin A expression at both transcript and protein levels, whereas LAMP2a, the rate-limiting factor of chaperone-mediated autophagy, was upregulated by inhibition of LAMP2a degradation. Furthermore, leptin promoted LAMP2a multimerization through the lysosomal mTORC2 (mTOR complex 2)/PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1)/AKT1 (Serine/threonine-protein kinase 1) pathway. These findings suggest that targeting leptin receptors can alleviate mammary gland cancer cell metastasis in dogs.

MIR-190B Alleviates Cell Autophagy and Burn-Induced Skeletal Muscle Wasting via Modulating PHLPP1/Akt/FoxO3A Signaling Pathway.

Cell autophagy is an important material recycling process and is involved in regulating many vital activities under both physiological and pathological conditions. However, the mechanism of autophagy regulating burn-induced skeletal muscle wasting still needs to be elucidated. The rat burn model with 30% total body surface area and L6 cell line were used in this study. An immunofluorescence assay was used to detect autophagic levels. MicroRNA array and real-time PCR were employed to measure miR-190b levels, and its influence on PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) protein translation was estimated using luciferase reporter assay. The expression levels of autophagy-related proteins were analyzed by Western blot. Skeletal muscle wasting was evaluated by the ratio of tibias anterior muscle weight to body weight. Our study demonstrates that burn injury promotes expression of the autophagy-related proteins light chain 3 (LC3) and Beclin-1, suppresses expression of Akt and Forkhead box O (FoxO) 3a protein phosphorylation, and increases PHLPP1 protein level which is required for Akt dephosphorylation. miR-190b, the regulator of PHLPP1 protein translation, also significantly decreases after burn injury. Ectopic expression of miR-190b in L6 myoblast cell downregulates PHLPP1 protein expression, elevates Akt and FoxO3a phosphorylation, and subsequently reduces cell autophagy. Finally, suppressing autophagy with 3-methyladenine represses the protein expression of LC3 and Beclin-1 and mitigates burn-induced skeletal muscle wasting. Burn injury induced skeletal muscle cell autophagy and subsequently resulted in skeletal muscle wasting via regulating miR-190b/PHLPP1/Akt/FoxO3a signaling pathway.

Identification of Key Hydroxymethylated Genes and Transcription Factors Associated with Alpha-Fetoprotein-Negative Hepatocellular Carcinoma.

DNA hydroxymethylation is one of the major epigenetic mechanisms mediating the development of several human cancers. This study aimed to identify key hydroxymethylated genes and transcription factors (TFs) associated with alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) using whole-genome DNA hydroxymethylation profiling. A total of 615 differentially hydroxymethylated regions (DHMRs) were identified from AFP-negative HCC tissues compared to adjacent normal tissues. DHMR-associated genes were significantly enriched in gene ontology functions associated with actin binding, cell leading edge, and blood vessel morphogenesis and pathways such as MAPK signaling pathway, neuroactive ligand-receptor interaction, and axon guidance. Moreover, protein-protein interaction (PPI) network analysis showed that PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) had higher degrees and were hub nodes. Furthermore, TF prediction analysis showed that TFs, such as nuclear factor I C (NFIC) and GATA binding protein 3 (GATA3), regulated many DHMR-associated genes. Our findings reveal that key hydroxymethylated genes such as PHLPP1 and SMARCA2, as well as TFs such as NFIC and GATA, may be involved in the development of AFP-negative HCC. These molecules may be potential biomarkers for AFP-negative HCC.

The tuberous sclerosis complex subunit TBC1D7 is stabilized by Akt phosphorylation–mediated 14-3-3 binding

The tuberous sclerosis complex (TSC) is a negative regulator of mTOR complex 1, a signaling node promoting cellular growth in response to various nutrients and growth factors. However, several regulators in TSC signaling still await discovery and characterization. Using pulldown and MS approaches, here we identified the TSC complex member, TBC1 domain family member 7 (TBC1D7), as a binding partner for PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), a negative regulator of Akt kinase signaling. Most TBC domain-containing proteins function as Rab GTPase-activating proteins (RabGAPs), but the crystal structure of TBC1D7 revealed that it lacks residues critical for RabGAP activity. Sequence analysis identified a putative site for both Akt-mediated phosphorylation and 14-3-3 binding at Ser-124, and we found that Akt phosphorylates TBC1D7 at Ser-124. However, this phosphorylation had no effect on the binding of TBC1D7 to TSC1, but stabilized TBC1D7. Moreover, 14-3-3 protein both bound and stabilized TBC1D7 in a growth factor-dependent manner, and a phospho-deficient substitution, S124A, prevented this interaction. The crystal structure of 14-3-3ζ in complex with a phospho-Ser-124 TBC1D7 peptide confirmed the direct interaction between 14-3-3 and TBC1D7. The sequence immediately upstream of Ser-124 aligned with a canonical β-TrCP degron, and we found that the E3 ubiquitin ligase β-TrCP2 ubiquitinates TBC1D7 and decreases its stability. Our findings reveal that Akt activity determines the phosphorylation status of TBC1D7 at the phospho-switch Ser-124, which governs binding to either 14-3-3 or β-TrCP2, resulting in increased or decreased stability of TBC1D7, respectively.

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness.

Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.

A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury

Calpain has been shown to be involved in neurodegeneration, and in particular in retinal ganglion cell (RGC) death resulting from increased intraocular pressure (IOP) and ischemia. However, the specific roles of the two major calpain isoforms, calpain-1 and calpain-2, in RGC death have not been investigated. Here, we show that calpain-1 and calpain-2 were sequentially activated in RGC dendrites after acute IOP elevation. By combining the use of a selective calpain-2 inhibitor (C2I) and calpain-1 KO mice, we demonstrated that calpain-1 activity supported survival, while calpain-2 activity promoted cell death of RGCs after IOP elevation. Calpain-1 activation cleaved PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and activated the Akt pro-survival pathway, while calpain-2 activation cleaved striatal-enriched protein tyrosine phosphatase (STEP) and activated STEP-mediated pro-death pathway in RGCs after IOP elevation. Systemic or intravitreal C2I injection to wild-type mice 2h after IOP elevation promoted RGC survival and improved visual function. Our data indicate that calpain-1 and calpain-2 play opposite roles in high IOP-induced ischemic injury and that a selective calpain-2 inhibitor could prevent acute glaucoma-induced RGC death and blindness.

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells.

In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors.

Abstract B110: The use of patient-derived xenograft models to explore new treatment strategies in uterine sarcomas

Abstract Background: Uterine leiomyosarcomas (uLMS) are rare, aggressive tumors. The limited benefit of current treatments emphasizes the need for new treatment modalities. Our aim is to gain insight into the molecular determinants of response to targeted and systemic therapies in uterine sarcomas, using pre-clinical models. Methods: Nine uLMS (uLMS1-9) patient-derived tumor xenograft (PDTX) models were established in collaboration with the PDTX platform. In the LMS1 model, we selected 6 treatment groups (+placebo group; 4 mice/group; 28 days) based on molecular findings and literature. First, SNP-array technique was used to detect copy number alterations. Heterozygous deletions were detected of phosphatase and tensin homolog (PTEN) and PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1), both negative regulators of the PI3K/mTOR pathway. Immunohistochemistry confirmed mTOR pathway activity through phospho-S6 ribosomal protein detection. Therefore, we selected the PI3K/mTOR inhibitor BEZ235. Second, pazopanib (inhibits PDGFR, VEGFR, c-KIT and FGFR) was recently approved for treatment of LMS. ULMS1 showed homogeneous expression of PDGFR. Third, histone deacetylase inhibitors have recently been shown to inhibit cell growth in many cancers, including LMS. Therefore, valproate was selected in single therapy, as well as in combination therapy with pazopanib and BEZ235. Last, trabectedin was included as state-of-the-art chemotherapy. Based on this pilot experiment, the uLMS1 model was again treated with BEZ235, trabectedin and the combination of both compounds in a larger cohort for 22 days (7-9 mice/group). Additionally, a second uLMS model (uLMS2) was treated with the same compounds for 22 days (5-6 mice/group). Results: In the uLMS1 pilot experiment, treatment with trabectedin and BEZ235 resulted in stable tumor volume, while other compounds showed no effect. No significant differences were noted, possibly due to the low number of mice used. Therefore, the experiment was repeated using only BEZ235, trabectedin and the combination treatment in a higher number of mice. Although BEZ235 and trabectedin showed minor reductions in tumor growth, the effects were not significant. However, in the uLMS2 model, BEZ235, trabectedin and the combination treatment all led to a highly significant reduction in tumor volume, while placebo-treated tumors grew as large as 4 times the starting volume. Placebo vs trabectedin, BEZ235 and the combination all showed p-values lower than 0.0001. The combination treatment showed a stronger effect than single-agent trabectedin (p = 0.0001) and single-agent BEZ235 (p = 0.0003). Conclusions: BEZ235, trabectedin and the combination of both compounds showed effect in a uterine sarcoma PDTX model. Next, their effects will be assessed in different uLMS models and responses will be linked to selected pathway activities, determined by gene/protein expression, protein activation and copy number alterations. Citation Format: Tine Cuppens, Els Hermans, Debby Thomas, Ellen Gommé, Matthieu Moisse, Diether Lambrechts, Frederic Amant. The use of patient-derived xenograft models to explore new treatment strategies in uterine sarcomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B110.

PHLPP1 phosphatase inhibition in hypothalamus restores insulin signaling and action and reduces adiposity in obese rats

Background Obesity results from imbalance between food intake and energy expenditure. The energy homeostasis is regulated by hypothalamic neurons that receive different neural, hormonal and metabolic signals. Insulin is one of the main hormones that regulate energy homeostasis and acts through a cascade of intracellular signaling that depends on the activation of several proteins, such as Akt. Our hypothesis is that PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1) inhibits Akt activity by dephosphorylating serine 473 residues, impairing the insulin action in the hypothalamus. However, PHLPP1 expression and the role played by it on the hypothalamus of diet induced obesity (DIO) animals are not fully understood.

MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1

Objectives: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.Design and methods: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.Results: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change ≥ 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.Conclusion: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.

Interactome of the negative regulator of nuclear import BRCA1-binding protein 2.

Although the negative regulator of nuclear import (NRNI) BRCA1 binding protein 2 (BRAP2) is highly expressed in testis, its role is largely unknown. Here we address this question by documenting the BRAP2 interactome from human testis, using the yeast 2-hybrid system to identify BRAP2-interacting proteins with roles in diverse cellular processes, including regulation of the actin cytoskeleton, ubiquitinylation, cell cycle/apoptosis and transcription. Interaction with BRAP2 in adult mouse testis with three of these, PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1), A-Kinase anchor protein (AKAP3) and DNA methyl transferase 1 (DNMT1), was confirmed by coimmunoprecipitation assays. BRAP2's ability to inhibit PHLPP1 and DNMT1 nuclear localisation was also confirmed by quantitative confocal microscopy. Importantly, the physiological relevance thereof was implied by the cytoplasmic localisation of PHLPP1, AKAP3 and DNMT1 in pachytene spermatocytes/round spermatids where BRAP2 is present at high levels, and nuclear localisation of PHLPP1 and DNMT1 in spermatogonia concomitant with lower levels of BRAP2. Interestingly, BRAP2 was also present in murine spermatozoa, in part colocalised with AKAP3. Together the results indicate for the first time that BRAP2 may play an important NRNI role in germ cells of the testis, with an additional, scaffold/structural role in mature spermatozoa.

Distinct Roles for μ-Calpain and m-Calpain in Synaptic NMDAR-Mediated Neuroprotection and Extrasynaptic NMDAR-Mediated Neurodegeneration

Prolonged calpain activation is widely recognized as a key component of neurodegeneration in a variety of pathological conditions. Numerous reports have also indicated that synaptic activation of NMDA receptors (NMDARs) provides neuroprotection against a variety of insults. Here, we report the paradoxical finding that such neuroprotection involves calpain activation. NMDAR activation in cultured rat cortical neurons was neuroprotective against starvation and oxidative stress-induced damage. It also resulted in the degradation of two splice variants of PH domain and Leucine-rich repeat Protein Phosphatase 1 (PHLPP1), PHLPP1α and PHLPP1β, which inhibit the Akt and ERK1/2 pathways. Synaptic NMDAR-induced neuroprotection and PHLPP1 degradation were blocked by calpain inhibition. Lentiviral knockdown of PHLPP1 mimicked the neuroprotective effects of synaptic NMDAR activation and occluded the effects of calpain inhibition on neuroprotection. In contrast to synaptic NMDAR activation, extrasynaptic NMDAR activation had no effect on PHLPP1 and the Akt and ERK1/2 pathways, but resulted in calpain-mediated degradation of striatal-enriched protein tyrosine phosphatase (STEP) and neuronal death. Using μ-calpain- and m-calpain-selective inhibitors and μ-calpain and m-calpain siRNAs, we found that μ-calpain-dependent PHLPP1 cleavage was involved in synaptic NMDAR-mediated neuroprotection, while m-calpain-mediated STEP degradation was associated with extrasynaptic NMDAR-induced neurotoxicity. Furthermore, m-calpain inhibition reduced while μ-calpain knockout exacerbated NMDA-induced neurotoxicity in acute mouse hippocampal slices. Thus, synaptic NMDAR-coupled μ-calpain activation is neuroprotective, while extrasynaptic NMDAR-coupled m-calpain activation is neurodegenerative. These results help to reconcile a number of contradictory results in the literature and have critical implications for the understanding and potential treatment of neurodegenerative diseases.

NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis

The biological functions of nuclear factor κB1 (NFκB1; p50) have not been studied as often as those of other members of the NFκB family due to its lack of a transcriptional domain. Our recent studies showed that p50 functions as an apoptotic mediator via its inhibition of GADD45α protein degradation and increase in p53 protein translation. Here we report a novel function of p50 in its regulation of superoxide dismutase 2 (SOD2) transcription via an NFκB-independent pathway. We find that deletion of p50 in mouse embryonic fibroblasts (MEFs; p50(-/-)) up-regulates SOD2 expression at both protein and mRNA levels. SOD2 promoter-driven luciferase is also up-regulated in p50(-/-) cells compared with wild-type (WT) MEF (p50(+/+)) cells, suggesting p50 regulation of SOD2 at the transcriptional level. Our results also show that p50 deficiency specifically results in down-regulation of phosphorylation and increased transactivation of FoxO3a compared with WT cells. Further studies indicate that p50-down-regulated FoxO3a phosphorylation is mediated by activated Akt via up-regulation of microRNA 190 (miR190), in turn inhibiting PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) translation. Together our studies identify a novel p50 function in the regulation of SOD2 transcription by modulating the miR190/PHLPP1/Akt-FoxO3a pathway, which provides significant insight into the physiological function of p50.

Abstract 3081: Crosstalk between Runx2 regulatory network and PI3K/Akt signaling pathway in breast cancer cells

Abstract The Runt-related transcription factor Runx2 is essential for skeletal development but is also aberrantly expressed in several cancers (e.g., breast, prostate and osteosarcoma) where it promotes cell migration, invasive and growth properties of cancer cells. The phosphatidylinositol 3′ kinase (PI3K)/Akt signaling pathway is linked to Runx2-dependent skeletogenesis, however, the mechanisms of Runx2 role in PI3K-Akt signaling in breast cancers, and its implication in cancer progression remains under investigated. To mechanistically determine the function of Runx2 in epidermal growth factor (EGF)-induced PI3K/Akt signaling and concomitantly ensuing downstream signaling events, we modulated Runx2 expression levels in immortalized normal MCF-10A and invasive MDA-MB-231 cells via lentiviral vector-mediated gene delivery. The Runx2 over-expression in EGF-stimulated MCF-10A cells increased the cellular response towards PI3K inhibitor LY294002 as indicated by a decline in Akt (Serine 473) phosphorylation (pAkt) levels. This effect could be restored by Runx2 suppression indicating the specificity of Runx2 function in Akt regulation. In MDA-MB-231 cells, Runx2 over-expression and, surprisingly, suppression profoundly inhibited pAkt suggesting that a threshold level of Runx2 is required for phosphorylation of Akt. The Runx2-mediated decline in pAkt was completely reversed by the Runx2-DNA binding mutant over-expression indicating that Runx2 DNA binding domain is essential for Akt inhibition. To further dissect the mechanism of Runx2-mediated regulation of pAkt levels in MDA-MB-231 cells, we examined the protein levels of phosphatases and kinases associated with PI3K/Akt signaling pathway. These analyses revealed that PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1) levels were directly responsive to Runx2. Chromatin immunoprecipitation studies showed Runx2 recruitment on the proximal promoter of PHLPP1 suggesting that Runx2 mediates its effect on Akt activity, in part by regulating PHLPP1 expression. Furthermore, Runx2 overexpression increased nuclear translocation of a forkhead box transcription factor FoxO1, a downstream molecule of PI3K/Akt signaling indicating an indirect Runx2 affect on FoxO1 transcriptional activity in MDA-MB-231 cells as examined by western blot analysis and immunofluorescence studies. Together, our results identified clinically relevant and novel mechanisms of Runx2 regulatory network in PI3K/Akt signaling pathway that could have important consequences in targeting breast cancer-associated cell survival and invasive properties. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3081. doi:1538-7445.AM2012-3081

Regional hippocampal differences in AKT survival signaling across the lifespan: implications for CA1 vulnerability with aging

Distinct neuronal populations differ by the degree of damage caused from cellular stress. Hippocampal neurons of area CA1 are especially vulnerable to several stressors that increase with advanced age. We show here that survival signaling, as measured by activated AKT, was significantly reduced in the nuclear CA1 region across the lifespan compared to CA3. In agreement with these findings the pro-apoptotic protein, and AKT nuclear substrate, FOXO3a was significantly higher in CA1. Further, regional differences in PHLPP1, a recently discovered inhibitor of AKT, inversely correlated with nuclear phosphorylated AKT at Ser473. Together our data suggest that regional differences in nuclear levels of activated AKT may contribute to regional differences in hippocampal vulnerability, and implicate PHLPP1 as a potential target for therapeutic intervention to improve hippocampal health.