PTENless means more

AbstractRecent studies indicate that certain key molecules that are vital for various developmental processes, such as Wnt, Shh, and Notch, cause cancer when dysregulated. PTEN, a tumor suppressor that antagonizes the PI3 kinase pathway, is the newest one on the list. The biological function of PTEN is evolutionarily conserved from C. elegans to humans, and the PTEN-controlled signaling pathway regulates cellular processes crucial for normal development, including cell proliferation, soma growth, cell death, and cell migration. In this review, we will focus on the function of PTEN in murine development and its role in regulating stem cell self-renewal and proliferation. We will summarize the organomegaly phenotypes associated with Pten tissue-specific deletion and discuss how PTEN controls organ size, a fundamental aspect of development. Last, we will review the role of PTEN in hormone-dependent, adult-onset mammary and prostate gland development

Transcriptional Regulation by ERR and Its Role in NAFLD Pathogenesis

Members of estrogen-related receptors (ERRs) are orphan nuclear receptors (NRs) that play primary roles in mitochondrial biogenesis and bioenergetics. The ERRs regulate a range of cellular functions, including oxidative phosphorylation (OXPHOS) as well as glucose and lipid metabolism. ERRs are considered important targets for the treatment of metabolic diseases, particularly type II diabetes (T2D), insulin resistance (IR) and obesity. In this review, we will overview the transcriptional network regulated by the members of ERR transcriptional factors and elaborate on the regulation of ERR via its binding to PGC-1α, the primary co-activator of ERR as well as post-translational regulation of ERRs by upstream kinase signals. Recent development in ERR’s cellular function has identified lipid metabolism/lipogenesis as a process that ERR regulates, and this function significantly impacts metabolic syndrome. Here, we will focus on their roles in lipid metabolic regulation and discuss the in vivo functions of ERRs in the development of non-alcoholic fatty liver disease (NAFLD), a comorbid metabolic syndrome concurrent with T2D, IR as well as obesity. Finally, we will explore ERRs as potential therapeutic targets by discussing the ligands that serve as antagonist/agonists for ERRs as well as efforts that target DNA binding of ERR as a transcriptional factor

PTEN: Tumor Suppressor and Metabolic Regulator

Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is a dual phosphatase with both protein and lipid phosphatase activities. PTEN was first discovered as a tumor suppressor with growth and survival regulatory functions. In recent years, the function of PTEN as a metabolic regulator has attracted significant attention. As the lipid phosphatase that dephosphorylates phosphatidylinositol-3, 4, 5-phosphate (PIP3), PTEN reduces the level of PIP3, a critical 2nd messenger mediating the signal of not only growth factors but also insulin. In this review, we introduced the discovery of PTEN, the PTEN-regulated canonical and nuclear signals, and PTEN regulation. We then focused on the role of PTEN and PTEN-regulated signals in metabolic regulation. This included the role of PTEN in glycolysis, gluconeogenesis, glycogen synthesis, lipid metabolism as well as mitochondrial metabolism. We also included how PTEN and PTEN regulated metabolic functions may act paradoxically toward insulin sensitivity and tumor metabolism and growth. Further understanding of how PTEN regulates metabolism and how such regulations lead to different biological outcomes is necessary for interventions targeting at the PTEN-regulated signals in either cancer or diabetes treatment

Brain metabolic and functional alterations in a liver-specific PTEN knockout mouse model.

Insulin resistance-as observed in aging, diabetes, obesity, and other pathophysiological situations, affects brain function, for insulin signaling is responsible for neuronal glucose transport and control of energy homeostasis and is involved in the regulation of neuronal growth and synaptic plasticity. This study investigates brain metabolism and function in a liver-specific Phosphatase and Tensin Homologue (Pten) knockout mouse model (Liver-PtenKO), a negative regulator of insulin signaling. The Liver-PtenKO mouse model showed an increased flux of glucose into the liver-thus resulting in an overall hypoglycemic and hypoinsulinemic state-and significantly lower hepatic production of the ketone body beta-hydroxybutyrate (as compared with age-matched control mice). The Liver-PtenKO mice exhibited increased brain glucose uptake, improved rate of glycolysis and flux of metabolites in the TCA cycle, and improved synaptic plasticity in the hippocampus. Brain slices from both control- and Liver-PtenKO mice responded to the addition of insulin (in terms of pAKT/AKT levels), thereby neglecting an insulin resistance scenario. This study underscores the significance of insulin signaling in brain bioenergetics and function and helps recognize deficits in diseases associated with insulin resistance

Emerging signals regulating liver tumor initiating cells

Tumor initiating cells (TICs) have been identified as cells that account for tumor heterogeneity. Recent studies demonstrated that genes controlling stem cell biology play key roles in maintaining TICs and promote their development into cancer. In this review, we summarize findings from human and animal studies that indicate the presence of TICs during liver cancer development. Markers identified for liver development and regeneration are used to identify liver cancer TICs. Expression of these markers is often upregulated in human hepatocellular carcinoma (HCC) specimen. Using flow cytometry analysis and lineage tracing approaches, the presence of TICs is confirmed. Expression of TIC markers and the presence of TICs are also observed in genetically modified animals that target genes that are frequently altered in human HCC. The presence of these TICs represents a major challenge for therapeutic development. Elucidating signals that can regulate the fate, transformation and growth of liver TICs is an emerging need in liver research. Sex-determining region Y-box 9 (SOX9) has recently become an important marker for liver TICs. Here, we summarize the role of SOX9 in TICs and its potential interaction with other signals. This includes the Notch-Numb signal that controls asymmetrical-symmetrical cell division, Wnt-β-catenin signal that maintains cell fate and transforming growth factor (TGF)-β signal that acts as upstream inducers. Keywords: Liver cancer, Hepatocellular carcinoma (HCC), Tumor initiating cells (TICs), Sex-determining region Y-box 9 (SOX9), β-catenin, Notch, Numb, Transforming growth factor (TGF)-

Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma

SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors

Insulin Hypersensitivity and Resistance to Streptozotocin-Induced Diabetes in Mice Lacking PTEN in Adipose Tissue

In adipose tissue, insulin controls glucose and lipid metabolism through the intracellular mediators phosphatidylinositol 3-kinase and serine-threonine kinase AKT. Phosphatase and a tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, is hypothesized to inhibit the metabolic effects of insulin. Here we report the generation of mice lacking PTEN in adipose tissue. Loss of Pten results in improved systemic glucose tolerance and insulin sensitivity, associated with decreased fasting insulin levels, increased recruitment of the glucose transporter isoform 4 to the cell surface in adipose tissue, and decreased serum resistin levels. Mutant animals also exhibit increased insulin signaling and AMP kinase activity in the liver. Pten mutant mice are resistant to developing streptozotocin-induced diabetes. Adipose-specific Pten deletion, however, does not alter adiposity or plasma fatty acids. Our results demonstrate that in vivo PTEN is a potent negative regulator of insulin signaling and insulin sensitivity in adipose tissue. Furthermore, PTEN may be a promising target for nutritional and/or pharmacological interventions aimed at reversing insulin resistance

Essential Role of AKT-1/Protein Kinase Bα in PTEN-Controlled Tumorigenesis

PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP(3)) accumulation, enhanced entry into S phase, and better cell survival. Since PIP(3) controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten(−/−) ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten(−/−) ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten(−/−) ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis