Roles of phosphatase and tensin homolog in skeletal muscle

The phosphatase and tensin homolog (PTEN), originally identified as a tumor suppressor, is an important regulator of the PI3K–Akt pathway. PTEN plays crucial roles in various cellular processes, including cell survival, cell growth, cell proliferation, cell differentiation, and cell metabolism. In metabolic tissues, PTEN expression affects insulin sensitivity and glucose homeostasis. In skeletal muscle, the deletion of PTEN regulates muscle development and protects the mutant mice from insulin resistance and diabetes. Notably, the regulatory role of PTEN in skeletal muscle stem cells has been recently reported. In this review, we mainly discuss the role of PTEN in regulating the development, glucose metabolism, stem cell fate decision, and regeneration of skeletal muscle.     

PTEN: a default gate-keeping tumor suppressor with a versatile tail

The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation to ensure its proper function. Defects in PTEN regulation have a profound impact on carcinogenesis. In this review, we briefly discuss recent advances concerning PTEN regulation and how such knowledge facilitates our understanding and further exploration of PTEN biology. The carboxyl-tail of PTEN, which appears to be associated with multiple types of posttranslational regulation, will be under detailed scrutiny. Further, a comparative analysis of PTEN and p53 suggests while p53 needs to be activated to suppress tumorigenesis （a dormant gatekeeper）, PTEN is probably a constitutive surveillant against cancer development, thus a default gatekeeper.     

Akt pathway as a target for therapeutic intervention in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common form of cancer worldwide. One frequent alteration found in this type of cancer is overactivation of the PI3K/PTEN/mTOR pathway, of which protein kinase B (PKB)/Akt is a central key element, controlling important cellular processes such as metabolism, cell size, proliferation and apoptosis, ultimately regulating cell growth and survival. Thus, drugs that target Akt directly or elements of the pathway are plausible candidates for cancer treatment. Accordingly, numerous clinical trials in various phases are being performed for these drugs. In this review, we discuss the tumorigenic capacity of Akt and focus on its role in HNSCC, paying special attention to the current efforts in treating this cancer in a more specific, Akt-targeted way, based on its primordial role in this type of cancer.     

PI3K/PTEN signaling in tumorigenesis and angiogenesis

The phosphatidyl inositol 3-kinase (PI3K) can be activated by a variety of extracellular signals and involved in a number of cellular processes including cell proliferation, survival, protein synthesis, and tumor growth. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is an antagonist of PI3K. The alterations of PI3K pathway such as activation of oncogenes, gene amplification, and inactivation of tumor suppressors, commonly occur in many human cancers. Angiogenesis is required for tumor growth and metastasis when the tumor reaches more than 1 mm in diameter. Recent studies have shown that PI3K and Akt play an important role in regulating tumor growth and angiogenesis through VEGF and HIF-1 expression. PI3K regulates the expression of these two proteins through HDM2 and p70S6K1 in human cancer cells. The frequent dysregulation of the PI3K/PTEN pathway in human cancer demonstrates that this pathway is an appropriate target for cancer therapeutics. In this review, we describe the recent advances in understanding the PI3K/PTEN pathway, the role and mechanism of PI3K in regulating tumor growth and angiogenesis, and the potential therapeutic opportunities for targeting this pathway for cancer treatment.     

PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development.

Mutations in the tumor suppressor gene PTEN (MMAC1/TEP1) are associated with a large number of human cancers and several autosomal-dominant disorders. Mice mutant for PTEN die at early embryonic stages and the mutant embryonic fibroblasts display decreased sensitivity to cell death. Overexpression of PTEN in different mammalian tissue culture cells affects various processes including cell proliferation, cell death and cell migration. We have characterized the Drosophila PTEN gene and present evidence that both inactivation and overexpression of PTEN affect cell size, while overexpression of PTEN also inhibits cell cycle progression at early mitosis and promotes cell death during eye development in a context-dependent manner. Furthermore, we have shown that PTEN acts in the insulin signaling pathway and all signals from the insulin receptor can be antagonized by either Drosophila or human PTEN, suggesting a potential means for alleviating symptoms associated with altered insulin signaling.     

Dispensable role of PTEN in mouse spermatogenesis

PTEN (phosphatase and tensin homologue deleted on chromosome ten) plays critical roles in multiple cellular processes, including cell proliferation, survival, migration and transformation. A role of PTEN in mammalian spermatogenesis, however, has not been explored. To address this question, we generated a mouse model with PTEN conditional knockout in postnatal male germ cells. We found that spermatogenesis was normal in PTEN-deleted male germ cells. PTEN conditional mutant males produced sperm and sired offspring as competently as wild-type littermates. Moreover, our biochemical analysis also indicated that the Akt (acutely transforming retrovirus AKT8 in rodent T cell lymphoma) signalling pathway was not affected in mutant testis. Taken together, these findings demonstrate that PTEN is dispensable in mouse spermatogenesis.     

Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways

The control of cell and organ growth is fundamental to the development of multicellular organisms. Here, we show that dPTEN, a Drosophila homolog of the mammalian PTEN tumor suppressor gene, plays an essential role in the control of cell size, cell number, and organ size. In mosaic animals, dPTEN(-) cells proliferate faster than their heterozygous siblings, show an autonomous increase in cell size, and form organs of increased size, whereas overexpression of dPTEN results in opposite phenotypes. The loss-of-function phenotypes of dPTEN are suppressed by mutations in the PI3K target Dakt1 and the translational initiation factor eif4A, suggesting that dPTEN acts through the PI3K signaling pathway to regulate translation. Although activation of PI3K and Akt has been reported to increase rates of cellular growth but not proliferation, loss of dPTEN stimulates both of these processes, suggesting that PTEN regulates overall growth through PI3K/Akt-dependent and -independent pathways. Furthermore, we show that dPTEN does not play a major role in cell survival during Drosophila development. Our results provide a potential explanation for the high frequency of PTEN mutation in human cancer.     

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

Phosphatase and tensin homolog (PTEN) is an important tumor-suppressor gene which constitutes an important PI3K/Akt pathway by regulating the signaling of multiple biological processes, including apoptosis, metabolism, cell proliferation, and cell growth has been gaining increasing attention. However, the role of PTEN in regulating apoptosis of canine mammary tumors cells still needs further investigation. In this experiment, the effect of PTEN on proliferation and apoptosis in canine mammary tumors (CMT) cells was analyzed. As a result, gene and protein expression levels of apoptosis-related genes were detected. Eukaryotic expression vector pcDNA3.1+-PTEN were successfully constructed and stably transferred into canine CMT cells after geneticin (G418) selection. After pcDNA3.1+-PTEN transfection, compared with control group, the cells proliferation was inhibited and the cell apoptosis was increased in CMT cells. The expression of p-Akt was decreased and the apoptosis-related genes, such as caspase-3, caspase-9, and Bax, were increased. These data serve to demonstrate the function of PTEN on apoptosis and gene regulatory in PI3K/Akt pathway in CMT cells. Collectively, our data link the tumor-suppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signaling molecules whose signal target is the functional inactivation of the apoptosis gene product.     

经典WNT信号通路与哺乳动物肺器官发育

肺器官发育是上皮和问充质相互作用的过程,由多条信号通路共同调控。已知经典WNT信号通路对细胞的增殖、凋亡和分化起着重要的调控作用,在小鼠等模式生物上研究发现,它也参与了哺乳动物肺器官发育的调控过程。综述近年来经典WNT信号通路成员在哺乳动物肺器官发育过程中的表达变化、作用功能及表达异常可能诱发的肺部疾病,以期为研究经典WNT信号通路调控人类肺器官发育的分子机制及相关肺部疾病的诊治奠定基础。     

Proteomic studies of rat tibialis anterior muscle during postnatal growth and development

Phosphoinositide 3-kinase (PI3K) pathway exerts its effects through Akt, its downstream target molecule, and thereby regulates various cell functions including cell proliferation, cell transformation, apoptosis, tumor growth, and angiogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the PI3K/Akt pathway. However, the mechanism by PI3K/PTEN signaling regulates angiogenesis and tumor growth in vivo remains to be elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis. The effect of PTEN on VEGF-mediated signal in pancreatic cancer is unknown. This study aimed to determine the effect of PTEN on both the expression of VEGF and angiogenesis. Toward that end, we used the siRNA knockdown method to specifically define the role of PTEN in the expression of VEGF and angiogenesis. We found that siRNA-mediated inhibition of PTEN gene expression in pancreatic cancer cells increase their VEGF secretion, up-modulated the proliferation, and migration of co-cultured vascular endothelial cell and enhanced tubule formation by HUVEC. In addition, PTEN modulated VEGF-mediated signaling and affected tumor angiogenesis through PI3K/Akt/VEGF/eNOS pathway.     

The mechanism of action of the tumour suppressor gene PTEN

Intracellular levels of phosphorylation are regulated by the coordinated action of protein kinases and phosphatases. Disregulation of this balance can lead to cellular transformation. Here we review knowledge of the mechanisms of one protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in tumorigenesis and signal transduction. PTEN plays an important role in the phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits downstream targets mainly protein kinase B (PKB/Akt), cell survival and proliferation. PTEN contributes to cell cycle regulation by blockade of cells entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and motility by regulation of the extracellular signal-related kinase - mitogen activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal adhesion kinase (FAK). We also emphasize the increasingly important role that PTEN has from an evolutionary point of view. A number of PTEN functions have been elucidated but more information is needed for utilization in clinical application and potential cancer therapy.     

MicroRNAs as important players in regulating cancer through PTEN/PI3K/AKT signalling pathways

Cancer being the leading cause of mortality has become a great threat worldwide. Current cancer therapeutics lack specificity and have side effects due to a lack of understanding of the molecular mechanisms and signalling pathways involved in carcinogenesis. In recent years, researchers have been focusing on several signalling pathways to pave the way for novel therapeutics. The PTEN/PI3K/AKT pathway is one of the important pathways involved in cell proliferation and apoptosis, leading to tumour growth. In addition, the PTEN/PI3K/AKT axis has several downstream pathways that could lead to tumour malignancy, metastasis and chemoresistance. On the other hand, microRNAs (miRNAs) are important regulators of various genes leading to disease pathogenesis. Hence studies of the role of miRNAs in regulating the PTEN/PI3K/AKT axis could lead to the development of novel therapeutics for cancer. Thus, in this review, we have focused on various miRNAs involved in the carcinogenesis of various cancer via the PTEN/PI3K/AKT axis.     

Interleukin-1β/nuclear factor-κB signaling promotes osteosarcoma cell growth through the microRNA-181b/phosphatase and tensin homolog axis

So far, microRNA has attracted plenty of interest due to its role in tumorigenesis. Reportedly, miR-181b may be involved in the tumorigenesis of osteosarcoma (OS). In the current study, we attempted to investigate the detailed function and mechanism of miR-181b in OS carcinogenesis. Herein, miR-181a, miR-181b, miR-181c, and miR-181d expressions in OS tissues were higher than that in nontumor tissue samples as examined real-time polymerase chain reaction. Via direct targeting, miR-181b negatively regulated the expression of phosphatase and tensin homolog (PTEN), a well-known tumor suppressor. Furthermore, a small interfering RNA strategy was used to find that interleukin (IL)-1B and nuclear factor-κB (NF-κB) regulate miR-181b and PTEN expression. Consequently, the repression of PTEN by miR-181b promotes OS cell proliferation. In summary, our data support a critical role for NF-κB-dependent upregulation of miR-181b, which further inhibited PTEN expression and promoted the cell proliferation of OS cell lines. The above findings represent a new pathway for the repression of PTEN and the promotion of cell proliferation upon IL-1β induction.     

TSC1/TSC2 signaling in the CNS

Over the past several years, the study of a hereditary tumor syndrome, tuberous sclerosis complex (TSC), has shed light on the regulation of cellular proliferation and growth. TSC is an autosomal dominant disorder that is due to inactivating mutations in TSC1 or TSC2 and characterized by benign tumors (hamartomas) involving multiple organ systems. The TSC1/2 complex has been found to play a crucial role in an evolutionarily-conserved signaling pathway that regulates cell growth: the mTORC1 pathway. This pathway promotes anabolic processes and inhibits catabolic processes in response to extracellular and intracellular factors. Findings in cancer biology have reinforced the critical role for TSC1/2 in cell growth and proliferation. In contrast to cancer cells, in the CNS, the TSC1/2 complex not only regulates cell growth/proliferation, but also orchestrates an intricate and finely tuned system that has distinctive roles under different conditions, depending on cell type, stage of development, and subcellular localization. Overall, TSC1/2 signaling in the CNS, via its multi-faceted roles, contributes to proper neural connectivity. Here, we will review the TSC signaling in the CNS.     

Phosphatase of Regenerating Liver 2 (PRL2) Is Essential for Placental Development by Down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and Activating Akt Protein

The PRL (phosphatase of regenerating liver) phosphatases are implicated in the control of cell proliferation and invasion. Aberrant PRL expression is associated with progression and metastasis of multiple cancers. However, the specific in vivo function of the PRLs remains elusive. Here we show that deletion of PRL2, the most ubiquitously expressed PRL family member, leads to impaired placental development and retarded growth at both embryonic and adult stages. Ablation of PRL2 inactivates Akt and blocks glycogen cell proliferation, resulting in reduced spongiotrophoblast and decidual layers in the placenta. These structural defects cause placental hypotrophy and insufficiency, leading to fetal growth retardation. We demonstrate that the tumor suppressor PTEN is elevated in PRL2-deficient placenta. Biochemical analyses indicate that PRL2 promotes Akt activation by down-regulating PTEN through the proteasome pathway. This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway.     

Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing beta cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of beta-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total beta-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in beta cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for beta-cell protection and regeneration therapies.