Human chromosome 1p35-p36 has long been suspected to harbor a tumor suppressor gene in pancreatic cancer and other tumors. We found that expression of rap1GAP, a gene located in this chromosomal region, is significantly downregulated in pancreatic cancer. Only a small percentage of preneoplastic pancreatic intraductal neoplasia lesions lost rap1GAP expression, whereas loss of rap1GAP expression occurred in 60% of invasive pancreatic cancers, suggesting that rap1GAP contributes to pancreatic cancer progression. In vitro and in vivo studies showed that loss of rap1GAP promotes pancreatic cancer growth, survival, and invasion, and may function through modulation of integrin activity. Furthermore, we showed a high frequency of loss of heterozygosity of rap1GAP in pancreatic cancer. Collectively, our data identify rap1GAP as a putative tumor suppressor gene in pancreatic cancer. (Cancer Res 2006; 66(2): 898-906)

Transforming growth factor ␤ (TGF␤) interacts with cell surface receptors to initiate a signaling cascade critical in regulating growth, differentiation, and development of many cell types. TGF␤ signaling involves activation of Smad proteins which directly regulate target gene expression. Here we show that Smad proteins also regulate gene expression by using a previously unrecognized pathway involving direct interaction with protein kinase A (PKA). PKA has numerous effects on growth, differentiation, and apoptosis, and activation of PKA is generally initiated by increased cellular cyclic AMP (cAMP). However, we found that TGF␤ activates PKA independent of increased cAMP, and our observations support the conclusion that there is formation of a complex between Smad proteins and the regulatory subunit of PKA, with release of the catalytic subunit from the PKA holoenzyme. We also found that the activation of PKA was required for TGF␤ activation of CREB, induction of p21 Cip1 , and inhibition of cell growth. Taken together, these data indicate an important and previously unrecognized interaction between the TGF␤ and PKA signaling pathways.Transforming growth factor beta (TGF␤) is one of a family of proteins that regulate a diverse array of biological functions including growth and differentiation, embryonic development, angiogenesis, and wound healing. Disruption of the ligands or components of this signaling pathway is associated with a number of human diseases, including cancer (2). The TGF␤ family includes activins, inhibins, bone morphogenetic proteins, and TGF␤. Signaling begins when TGF␤ binds to cell surface serine/threonine kinase receptors. TGF␤ binds to the type II TGF␤ receptor (RII), which then interacts with and phosphorylates the type I TGF␤ receptor (RI). Phosphorylation activates the intrinsic kinase activity of RI, making it possible for the receptor to phosphorylate and, thus, activate Smad proteins (Smads). To date, at least nine Smads have been cloned, and among them, the highly related Smad2 and Smad3 are specific effectors for TGF␤ signaling (24). Ligand binding to the TGF␤ receptor complex results in C-terminal phosphorylation of Smad2 and Smad3. Once phosphorylated, Smad2 and Smad3 dissociate from the receptor, bind to Smad4, and enter the nucleus. In the nucleus, heteromeric complexes of Smads function as effectors of Smad signaling by binding directly to DNA and/or by interacting with other DNA-binding proteins to target genes for transcriptional regulation.Recently, interactions of TGF␤ pathway components with effectors of other signaling pathways have been described. One potentially important interaction was suggested by a report that TGF␤ could activate cyclic AMP (cAMP)-dependent protein kinase (also known as protein kinase A, or PKA) through an unknown mechanism (40). PKA is a cytosolic, tetrameric holoenzyme that is composed of two regulatory subunits associated with two catalytic subunits (11,29,36,39). Elevation of intracellular cAMP levels causes binding of cAMP to the regulatory su...

CoO has been widely studied as a promising candidate as an anode material for lithium ion batteries. However, the huge volume change and structural strain associated with the Li insertion and extraction process leads to the pulverization and deterioration of the electrode, resulting in a poor performance in lithium ion batteries. In this paper, CoO rose-spheres obtained via hydrothermal technique are successfully embedded in graphene through an electrostatic self-assembly process. Graphene-embedded CoO rose-spheres (G-CoO) show a high reversible capacity, a good cyclic performance, and an excellent rate capability, e.g., a stable capacity of 1110.8 mAh g at 90 mA g (0.1 C), and a reversible capacity of 462.3 mAh g at 1800 mA g (2 C), benefitted from the novel architecture of graphene-embedded CoO rose-spheres. This work has demonstrated a feasible strategy to improve the performance of CoO for lithium-ion battery application.

This paper reports that Cu3P is capable of delivering high specific capacity as the cathode material for rechargeable aluminum-ion batteries.

The platelet-derived growth factor (PDGF) is a potent mitogen for murine fibroblasts. PDGF-stimulated cells express a set of immediate-early-response genes but require additional (progression) factors in serum to progress through the cell cycle. Serum-deprived cells are reversibly arrested in Go phase and fail to fully traverse the G1 phase of the cell cycle when stimulated by PDGF alone. We now report that serum-deprived normal rat kidney fibroblast (NRK) cells stimulated by either PDGF AA or PDGF BB homodimers undergo apoptotic cell death. Furthermore, we show that epidermal growth factor also induces apoptotic cell death in serum-deprived NRK cells, epidermal growth factor enhances the rate of apoptosis in PDGF-treated cells, and a progression factor (insulin) but not endogenously expressed Bcl-2 fully protects NRK cells from PDGF-stimulated apoptosis. The results indicate that PDGF induces apoptosis in growtharrested NRK cells and that the inability of NRK cells to transit the G1/S checkpoint is the critical determinant in establishing the genetic program(s) to direct the PDGF signal to apoptosis. The results suggest that polypeptide growth factors in vivo may signal cell fate positively or negatively in settings that limit the potential of cells to completely transit the cell cycle.