NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling.

Background: mTORC2 is a critical regulator of cytoskeleton organization, cell proliferation, and cancer cell survival. Activated mTORC2 induces maximal activation of Akt by phosphorylation of Ser-473, but regulation of Akt activity and signaling crosstalk upon growth factor stimulation are still unclear.

Results: We identified that NUAK1 regulates growth factor-dependent activation of Akt by two mechanisms.

The Sall2 transcription factor promotes cell migration regulating focal adhesion turnover and integrin β1 expression.

SALL2/Sall2 is a transcription factor associated with development, neuronal differentiation, and cancer. Interestingly, deficiency leads to failure of the optic fissure closure and neurite outgrowth, suggesting a positive role for SALL2/Sall2 in cell migration. However, in some cancer cells, deficiency is associated with increased cell migration.

Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Cells.

Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies.

SALL Proteins; Common and Antagonistic Roles in Cancer.

SALL proteins are a family of four conserved C2H2 zinc finger transcription factors that play critical roles in organogenesis during embryonic development. They regulate cell proliferation, survival, migration, and stemness; consequently, they are involved in various human genetic disorders and cancer. SALL4 is a well-recognized oncogene; however, SALL1-3 play dual roles depending on the cancer context and stage of the disease.

An environmental measurement for a dynamic and endogenous global environmental Kuznets curve in the global context.

Planetary boundaries (PB) is a novel conceptual framework that assesses the state of processes fundamental to the stability of the Earth system. Studies argue a non-linear relationship between economy and environmental degradation, known as the environmental Kuznets curve (EKC). We postulate this inverted-U association between PB and economic output in a worldwide sample.

Characterization of Gene Isoforms and Targets Across Cell Types Reveals Highly Conserved Networks.

The SALL2 transcription factor, an evolutionarily conserved gene through vertebrates, is involved in normal development and neuronal differentiation. In disease, SALL2 is associated with eye, kidney, and brain disorders, but mainly is related to cancer. Some studies support a tumor suppressor role and others an oncogenic role for SALL2, which seems to depend on the cancer type.

Cytosolic NUAK1 Enhances ATP Production by Maintaining Proper Glycolysis and Mitochondrial Function in Cancer Cells.

NUAK1 is an AMPK-related kinase located in the cytosol and the nucleus, whose expression associates with tumor malignancy and poor patient prognosis in several cancers. Accordingly, NUAK1 was associated with metastasis because it promotes cell migration and invasion in different cancer cells. Besides, NUAK1 supports cancer cell survival under metabolic stress and maintains ATP levels in hepatocarcinoma cells, suggesting a role in energy metabolism in cancer.

Inhibition of Hypothalamic MCT4 and MCT1-MCT4 Expressions Affects Food Intake and Alters Orexigenic and Anorexigenic Neuropeptide Expressions.

Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons.

Identification of a nuclear localization signal and importin beta members mediating NUAK1 nuclear import inhibited by oxidative stress.

NUAK1 is a serine/threonine kinase member of the AMPK-α family. NUAK1 regulates several processes in tumorigenesis; however, its regulation and molecular targets are still poorly understood. Bioinformatics analysis predicted that the majority of NUAK1 localizes in the nucleus.

DISC1 promotes translation maintenance during sodium arsenite-induced oxidative stress.

Variation in Disrupted-in-Schizophrenia 1 (DISC1) increases the risk for neurodegenerative diseases, schizophrenia, and other mental disorders. However, the functions of DISC1 associated with the development of these diseases remain unclear. DISC1 has been reported to inhibit Akt/mTORC1 signaling, a major regulator of translation, and recent studies indicate that DISC1 could exert a direct role in translational regulation.

A Trichostatin A (TSA)/Sp1-mediated mechanism for the regulation of SALL2 tumor suppressor in Jurkat T cells.

SALL2 is a transcription factor involved in development and disease. Deregulation of SALL2 has been associated with cancer, suggesting that it plays a role in the disease. However, how SALL2 is regulated and why is deregulated in cancer remain poorly understood.

SALL2 represses cyclins D1 and E1 expression and restrains G1/S cell cycle transition and cancer-related phenotypes.

SALL2 is a poorly characterized transcription factor that belongs to the Spalt-like family involved in development. Mutations on SALL2 have been associated with ocular coloboma and cancer. In cancers, SALL2 is deregulated and is proposed as a tumor suppressor in ovarian cancer.

Developmental SALL2 transcription factor: a new player in cancer.

SALL2, also known as Spalt-like transcription factor 2, is a member of the SALL family of transcription factors involved in development and conserved through evolution. Since its identification in 1996, findings indicate that SALL2 plays a role in neurogenesis, neuronal differentiation and eye development. Consistently, SALL2 deficiency associates with neural tube defects and coloboma, a congenital eye disease.

Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival.

Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin.

Rheb signaling and tumorigenesis: mTORC1 and new horizons.

Rheb is a conserved small GTPase that belongs to the Ras superfamily, and is mainly involved in activation of cell growth through stimulation of mTORC1 activity. Because deregulation of the Rheb/mTORC1 signaling is associated with proliferative disorders and cancer, inhibition of mTORC1 has been therapeutically approached. Although this therapy has proven antitumor activity, its efficacy is not as expected.

Rheb promotes cancer cell survival through p27Kip1-dependent activation of autophagy.

We previously found that the small GTPase Rheb regulates the cell-cycle inhibitor p27KIP1 (p27) in colon cancer cells by a mTORC1-independent mechanism. However, the biological function of the Rheb/p27 axis in cancer cells remains unknown. Here, we show that siRNA-mediated depletion of Rheb decreases survival of human colon cancer cells under serum deprivation.

Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.

SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors.

Consequences of interrupted Rheb-to-AMPK feedback signaling in tuberous sclerosis complex and cancer.

Rheb is a small GTPase primarily known for activating mammalian target of rapamycin complex 1 (mTORC1) and promoting cell growth in response to insulin and nutrients (amino acids, glucose). Shortage of glucose activates adenosine 5'-monophosphate-activated protein kinase (AMPK), which induces catabolic processes that produce ATP and suppresses energy-consuming anabolic reactions. As part of the latter response, AMPK activates the TSC1-TSC2 tumor suppressor complex, which in turn inhibits Rheb, thereby reducing mTORC1 activity and consequently suppressing protein synthesis.

M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells.

Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis.

Role of eIF3a in regulating cell cycle progression.

Translational control is an essential process in regulation of gene expression, which occurs at the initiation step performed by a number of translation initiation factor complexes. eIF3a (eIF3 p170) is the largest subunit of the eIF3 complex. eIF3a has been suggested to play roles in regulating translation of a subset of mRNAs and in regulating cell cycle progression and cell proliferation.

Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth.

By screening a fetal brain two-hybrid library with the death domain of the p75 neurotrophin receptor (NTR), we identified the Sall2 transcription factor as a novel interacting protein. Sall2 is a unique member of the Sall gene family, which is believed to be a tumour suppressor. Here, we show that Sall2 contains a p75NTR interaction domain not found in other Sall proteins and that p75NTR/Sall2 complexes co-immunoprecipitate from brain lysates.

The Sall2 transcription factor is a novel p75NTR binding protein that promotes the development and function of neurons.

Nerve growth factor (NGF) regulates the functions of neurons by binding the p75 neurotrophin receptor (p75NTR) and TrkA receptors. It is shown here that it has been found that the Sall2 transcription factor forms a complex with p75NTR. NGF dissociates Sall2 from p75NTR and also activates TrkA, which promotes translocation of Sall2 into the nucleus.

Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity.

The type 1 TNFR (TNFR1) contains a death domain through which it interacts with other death-domain proteins to promote cellular responses. However, signaling through death-domain proteins does not explain how TNFR1 induces the tyrosine phosphorylation of intracellular proteins, which are important to cellular responses induced by TNFR1. In this study, we show that TNFR1 associates with Jak2, c-Src, and PI3K in various cell types.

Enhanced peritoneal ovarian tumor dissemination by tissue transglutaminase.

Tissue transglutaminase (TG2) is involved in Ca(2+)-dependent aggregation and polymerization of proteins. We previously reported that TG2 mRNA is up-regulated in epithelial ovarian cancer (EOC) cells compared with normal ovarian epithelium. Here, we show overexpression of the TG2 protein in ovarian cancer cells and tumors and its secretion in ascites fluid and define its role in EOC.

Akt regulates basal and induced processing of NF-kappaB2 (p100) to p52.

NF-kappaB is a family of transcription factors important for innate and adaptive immunity. NF-kappaB is restricted to the cytoplasm by inhibitory proteins that are degraded when specifically phosphorylated, permitting NF-kappaB to enter the nucleus and activate target genes. Phosphorylation of the inhibitory proteins is mediated by an IkappaB kinase (IKK) complex, which can be composed of two subunits with enzymatic activity, IKKalpha and IKKbeta.