Showing papers in "Oncogene in 2005"

The p53 pathway: positive and negative feedback loops

Abstract: The p53 pathway responds to stresses that can disrupt the fidelity of DNA replication and cell division. A stress signal is transmitted to the p53 protein by post-translational modifications. This results in the activation of the p53 protein as a transcription factor that initiates a program of cell cycle arrest, cellular senescence or apoptosis. The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response. There are at least seven negative and three positive feedback loops described here, and of these, six act through the MDM-2 protein to regulate p53 activity. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene products. There are at least three different ubiquitin ligases that can regulate p53 in an autoregulatory manner: MDM-2, Cop-1 and Pirh-2. The meaning of this redundancy and the relative activity of each of these feedback loops in different cell types or stages of development remains to be elucidated. The interconnections between signal transduction pathways will play a central role in our understanding of cancer.

TGF-beta and epithelial-to-mesenchymal transitions.

Abstract: Remarkable phenotype plasticity of epithelial cells underlies morphogenesis, epithelial repair and tumor invasiveness. Detailed understanding of the contextual cues and molecular mediators that control epithelial plasticity will be required in order to develop viable therapeutic approaches targeting epithelial-to-mesenchymal transition (EMT), an advanced manifestation of epithelial plasticity. Members of the transforming growth factor (TGF-β) family of growth factors can initiate and maintain EMT in a variety of biological systems and pathophysiological context by activating major signaling pathways and transcriptional regulators integrated in extensive signaling networks. Here we will review the distinct physiological contexts of EMT and the underlying molecular signaling networks controlled by TGF-β.

Perturbations of the AKT signaling pathway in human cancer

Abstract: AKT/PKB (protein kinase B) kinases mediate signaling pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase AKT kinases regulate diverse cellular processes including cell proliferation and survival, cell size and response to nutrient availability, tissue invasion and angiogenesis Many oncoproteins and tumor suppressors implicated in cell signaling/metabolic regulation converge within the AKT signal transduction pathway in an equilibrium that is altered in many human cancers by activating and inactivating mechanisms, respectively, targeting these inter-related proteins We review a burgeoning literature implicating aberrant AKT signaling in many sporadic human cancers as well as in several dominantly inherited cancer syndromes known as phakomatoses The latter include disorders caused by germline mutations of certain tumor suppressor genes, that is, PTEN, TSC2/TSC1, LKB1, NF1, and VHL, encoding proteins that intersect with the AKT pathway We also review various pathogenic mechanisms contributing to activation of the AKT pathway in human malignancy as well as current pharmacologic strategies to target therapeutically components of this pathway

FOXO transcription factors at the interface between longevity and tumor suppression.

Abstract: A wide range of human diseases, including cancer, has a striking age-dependent onset. However, the molecular mechanisms that connect aging and cancer are just beginning to be unraveled. FOXO transcription factors are promising candidates to serve as molecular links between longevity and tumor suppression. These factors are major substrates of the protein kinase Akt. In the presence of insulin and growth factors, FOXO proteins are relocalized from the nucleus to the cytoplasm and degraded via the ubiquitin-proteasome pathway. In the absence of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest, stress resistance, or apoptosis. Stress stimuli also trigger the relocalization of FOXO factors into the nucleus, thus allowing an adaptive response to stress stimuli. Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity. Emerging evidence also suggests that FOXO factors play a tumor suppressor role in a variety of cancers. Thus, FOXO proteins translate environmental stimuli into changes in gene expression programs that may coordinate organismal longevity and tumor suppression.

Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways.

Abstract: Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways

Global epidemiology of HTLV-I infection and associated diseases.

Abstract: Epidemiologic aspects of human T-lymphotropic virus type I (HTLV-I) infection have been thoroughly studied over the course of approximately 25 years since its first description. The geographic distribution of the virus has been defined, with Japan, Africa, Caribbean islands and South America emerging as the areas of highest prevalence. The reasons for HTLV-I clustering, such as the high ubiquity in southwestern Japan but low prevalence in neighboring regions of Korea, China and eastern Russia are still unknown. The major modes of transmission are well understood, although better quantitative data on the incidence of transmission, and on promoting/inhibiting factors, are needed. Epidemiologic proof has been obtained for HTLV-I's causative role in major disease associations: adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-associated uveitis and infective dermatitis. However, more and better studies are needed for other apparent disease outcomes such as rheumatologic, psychiatric and infectious diseases. Since curative treatment of ATL and HAM/TSP is lacking and a vaccine is unavailable, the social and financial cost for the individual, his/her family and the health system is immense. For this reason, public health interventions aimed at counseling and educating high-risk individuals and populations are of paramount importance.

DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells.

Abstract: Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal transition (EMT) in embryonic development and cancer progression. Using the EpFosER mammary tumour model we show that during EMT, upregulation of the transcriptional regulator deltaEF1 coincided with transcriptional repression of E-cadherin. Ectopic expression of deltaEF1 in epithelial cells was sufficient to downregulate E-cadherin and to induce EMT. Analysis of E-cadherin promoter activity and chromatin immunoprecipitation identified deltaEF1 as direct transcriptional repressor of E-cadherin. In human cancer cells, transcript levels of deltaEF1 correlated directly with the extent of E-cadherin repression and loss of the epithelial phenotype. The protein was enriched in nuclei of human cancer cells and physically associated with the E-cadherin promoter. RNA interference-mediated downregulation of deltaEF1 in cancer cells was sufficient to derepress E-cadherin expression and restore cell to cell adhesion, suggesting that deltaEF1 is a key player in late stage carcinogenesis.

The E2F transcriptional network: old acquaintances with new faces.

Abstract: The E2 factor (E2F) family of transcription factors are downstream targets of the retinoblastoma protein. E2F factors have been known for several years to be important regulators of S-phase entry. Recent studies have improved our understanding of the molecular mechanisms of action used by this transcriptional network. In addition, they have given us an appreciation of the fact that E2F has functions that reach beyond G1/S control and impact cell proliferation in several different ways. The discovery of new family members with unusual properties, the unexpected phenotypes of mutant animals, a diverse collection of biological activities, a large number of new putative target genes and the new modes of transcriptional regulation have all contributed to an increasingly complex view of E2F function. In this review, we will discuss these recent developments and describe how they are beginning to shape a new and revised picture of the E2F transcriptional program.

Identification of molecular apocrine breast tumours by microarray analysis

Abstract: Previous microarray studies on breast cancer identified multiple tumour classes, of which the most prominent, named luminal and basal, differ in expression of the oestrogen receptor alpha gene (ER). We report here the identification of a group of breast tumours with increased androgen signalling and a 'molecular apocrine' gene expression profile. Tumour samples from 49 patients with large operable or locally advanced breast cancers were tested on Affymetrix U133A gene expression microarrays. Principal components analysis and hierarchical clustering split the tumours into three groups: basal, luminal and a group we call molecular apocrine. All of the molecular apocrine tumours have strong apocrine features on histological examination (P=0.0002). The molecular apocrine group is androgen receptor (AR) positive and contains all of the ER-negative tumours outside the basal group. Kolmogorov-Smirnov testing indicates that oestrogen signalling is most active in the luminal group, and androgen signalling is most active in the molecular apocrine group. ERBB2 amplification is commoner in the molecular apocrine than the other groups. Genes that best split the three groups were identified by Wilcoxon test. Correlation of the average expression profile of these genes in our data with the expression profile of individual tumours in four published breast cancer studies suggest that molecular apocrine tumours represent 8-14% of tumours in these studies. Our data show that it is possible with microarray data to divide mammary tumour cells into three groups based on steroid receptor activity: luminal (ER+ AR+), basal (ER- AR-) and molecular apocrine (ER- AR+).

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

Abstract: Mice deficient in CuZn superoxide dismutase (CuZnSOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1−/− mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1−/− and age-matched +/+ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1−/− mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.

Pocket proteins and cell cycle control.

Abstract: The retinoblastoma protein (pRB) and the pRB-related p107 and p130 comprise the 'pocket protein' family of cell cycle regulators. These proteins are best known for their roles in restraining the G1-S transition through the regulation of E2F-responsive genes. pRB and the p107/p130 pair are required for the repression of distinct sets of genes, potentially due to their selective interactions with E2Fs that are engaged at specific promoter elements. In addition to regulating E2F-responsive genes in a reversible manner, pocket proteins contribute to silencing of such genes in cells that are undergoing senescence or differentiation. Pocket proteins also affect the G1-S transition through E2F-independent mechanisms, such as by inhibiting Cdk2 or by stabilizing p27(Kip1), and they are implicated in the control of G0 exit, the spatial organization of replication, and genomic rereplication. New insights into pocket protein regulation have also been obtained. Kinases previously thought to be crucial to pocket protein phosphorylation have been shown to be redundant, and new modes of phosphorylation and dephosphorylation have been identified. Despite these advances, much remains to be learned about the pocket proteins, particularly with regard to their developmental and tumor suppressor functions. Thus continues the story of the pocket proteins and the cell cycle.

Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways

Abstract: Vascular endothelial growth factor (VEGF) upregulation is induced by many receptor and intracellular oncogenic proteins commonly activated in cancer, rendering molecular targeting of VEGF expression a complex challenge. While VEGF inducers abound, only two major transcription activators have been identified for its promoter: hypoxia inducible factor-1 (HIF-1) and signal transducer and activator of transcription (Stat3). Both HIF-1 expression and Stat3 activity are upregulated in diverse cancers. Here, we provide evidence that Stat3 is required for both basal and growth signal-induced expression of HIF-1. Moreover, induction of VEGF by diverse oncogenic growth stimuli, including IL-6R, c-Src, Her2/Neu, is attenuated in cells without Stat3 signaling. We further demonstrate that Stat3 regulates expression of Akt, which is required for growth signal-induced HIF-1 upregulation. Targeting Stat3 with a small-molecule inhibitor blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo. Furthermore, tumor cells' in vivo angiogenic capacity induced by IL-6R, which simultaneously activates Jak/STAT and PI3K/Akt pathways, is abrogated when Stat3 is inhibited. Activation of Stat3 signaling by various growth signaling is prevalent in diverse cancers. Results presented here demonstrate that Stat3 is an effective target for inhibiting tumor VEGF expression and angiogenesis.

PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas

Abstract: A recent report revealed that phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) gene is somatically mutated in several types of human cancer, suggesting the mutated PIK3CA gene as an oncogene in human cancers. However, because the previous report focused the mutational search primarily on colon cancers, the data on PIK3CA mutations in other types of human cancers have been largely unknown. Here, we performed mutational analysis of the PIK3CA gene by polymerase chain reaction-single-strand conformation polymorphism assay in 668 cases of common human cancers, including hepatocellular carcinomas, acute leukemias, gastric carcinomas, breast carcinomas, and non-small-cell lung cancers. We detected PIK3CA somatic mutations in 26 of 73 hepatocellular carcinomas (35.6%), 25 of 93 breast carcinomas (26.9%), 12 of 185 gastric carcinomas (6.5%), one of 88 acute leukemias (1.1%), and three of 229 non-small-cell lung cancers (1.3%). Some of the PIK3CA mutations were detected in the early lesions of breast cancer carcinoma, hepatocellular carcinoma, and gastric carcinomas, suggesting that PIK3CA mutation may occur independent of stage of the tumors. The high incidence and wide distribution of PIK3CA gene mutation in the common human cancers suggest that alterations of lipid kinase pathway by PIK3CA mutations contribute to the development of human cancers.

The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.

Abstract: Originally identified in Drosophila melanogaster, the Warts(Wts)/Lats protein kinase has been proposed to function with two other Drosophila proteins, Hippo (Hpo) and Salvador (Sav), in the regulation of cell cycle exit and apoptosis. In mammals, two candidate Warts/Lats homologs, termed Lats1 and Lats2, have been described, and the targeted disruption of LATS1 in mice increases tumor formation. Little, however, is known about the function and regulation of human Lats kinases. Here we report that human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2. Deletion analysis revealed that regulation of Lats1 occurs through the C-terminal, catalytic domain. Within this domain, two regulatory phosphorylation sites were identified by mass spectrometry. These sites, S909 in the activation loop and T1079 within a hydrophobic motif, have been highly conserved during evolution. Moreover, a direct interaction was observed between Mst2 and hWW45, a putative ortholog of Drosophila Sav. These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. Although the function of this pathway remains poorly understood in mammals, it is intriguing that, in Drosophila, it has been linked to development and tissue homeostasis.

SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation

Abstract: DNA tumor viruses such as simian virus 40 (SV40) express dominant acting oncoproteins that exert their effects by associating with key cellular targets and altering the signaling pathways they govern. Thus, tumor viruses have proved to be invaluable aids in identifying proteins that participate in tumorigenesis, and in understanding the molecular basis for the transformed phenotype. The roles played by the SV40-encoded 708 amino-acid large T antigen (T antigen), and 174 amino acid small T antigen (t antigen), in transformation have been examined extensively. These studies have firmly established that large T antigen's inhibition of the p53 and Rb-family of tumor suppressors and small T antigen's action on the pp2A phosphatase, are important for SV40-induced transformation. It is not yet clear if the Rb, p53 and pp2A proteins are the only targets through which SV40 transforms cells, or whether additional targets await discovery. Finally, expression of SV40 oncoproteins in transgenic mice results in effects ranging from hyperplasia to invasive carcinoma accompanied by metastasis, depending on the tissue in which they are expressed. Thus, the consequences of SV40 action on these targets depend on the cell type being studied. The identification of additional cellular targets important for transformation, and understanding the molecular basis for the cell type-specific action of the viral T antigens are two important areas through which SV40 will continue to contribute to our understanding of cancer.

ATP citrate lyase is an important component of cell growth and transformation

Abstract: Cell proliferation requires a constant supply of lipids and lipid precursors to fuel membrane biogenesis and protein modification. Cytokine stimulation of hematopoietic cells directly stimulates glucose utilization in excess of bioenergetic demand, resulting in a shift from oxidative to glycolytic metabolism. A potential benefit of this form of metabolism is the channeling of glucose into biosynthetic pathways. Here we report that glucose supports de novo lipid synthesis in growing hematopoietic cells in a manner regulated by cytokine availability and the PI 3 K/Akt signaling pathway. The net conversion of glucose to lipid is dependent on the ability of cells to produce cytosolic acetyl CoA from mitochondria-derived citrate through the action of ATP citrate lyase (ACL). Stable knockdown of ACL leads to a significant impairment of glucose-dependent lipid synthesis and an elevation of mitochondrial membrane potential. Cells with ACL knockdown display decreased cytokine-stimulated cell proliferation. In contrast, these cells resist cell death induced by either cytokine or glucose withdrawal. However, ACL knockdown significantly impairs Akt-mediated tumorigenesis in vivo. These data suggest that enzymes involved in the conversion of glucose to lipid may be targets for the treatment of pathologic cell growth.

The Akt/PKB pathway : molecular target for cancer drug discovery

Abstract: The serine/threonine kinase Akt/PKB pathway presents an exciting new target for molecular therapeutics, as it functions as a cardinal nodal point for transducing extracellular (growth factor and insulin) and intracellular (receptor tyrosine kinases, Ras and Src) oncogenic signals. In addition, alterations of the Akt pathway have been detected in a number of human malignancies. Ectopic expression of Akt, especially constitutively activated Akt, is sufficient to induce oncogenic transformation of cells and tumor formation in transgenic mice as well as chemoresistance. Akt has a wide range of downstream targets that regulate tumor-associated cell processes such as cell growth, cell cycle progression, survival, migration, epithelial-mesenchymal transition and angiogenesis. Blockage of Akt signaling results in apoptosis and growth inhibition of tumor cells with elevated Akt. The observed dependence of certain tumors on Akt signaling for survival and growth has wide implications for cancer therapy, offering the potential for preferential tumor cell killing. In the last several years, through combinatorial chemistry, high-throughput and virtual screening, and traditional medicinal chemistry, a number of inhibitors of the Akt pathway have been identified. This review focuses on ongoing translational efforts to therapeutically target the Akt pathway.

Cyclin E in normal and neoplastic cell cycles

Abstract: Cyclin E-Cdk2 has long been considered an essential and master regulator of progression through G1 phase of the cell cycle. Although recent mouse models have prompted a rethinking of cyclin E function in mammals, it remains clear that cyclin E impacts upon many processes central to cell division. Normal cells maintain strict control of cyclin E activity, and this is commonly disrupted in cancer cells. Moreover, cyclin E deregulation is thought to play a fundamental role in tumorigenesis. In this review, we discuss the regulation and functions of cyclin E in normal and neoplastic mammalian cells.

Akt-dependent transformation: there is more to growth than just surviving.

Abstract: Activation of the Akt/PKB protein kinase family triggers increases in cell size, metabolism and survival. Akt coordinately regulates these fundamental cellular processes through phosphorylation-dependent inactivation of tumor suppressors and activation of trophic signaling. Akt signaling stimulates transport and metabolism of both glucose and amino acids, which in turn support mTOR-dependent increases in protein translation. In addition, Akt activation directs cells to undertake a metabolic conversion from oxidative phosphorylation to aerobic glycolysis. Although this conversion promotes cell growth, it also renders cell survival dependent on a continuous supply of extracellular nutrients, which themselves are required regulatory elements in Akt signal transduction.

The life and death of DNA-PK

Abstract: Double-strand breaks (DSBs) arise endogenously during normal cellular processes and exogenously by genotoxic agents such as ionizing radiation (IR). DSBs are one of the most severe types of DNA damage, which if left unrepaired are lethal to the cell. Several different DNA repair pathways combat DSBs, with nonhomologous end-joining (NHEJ) being one of the most important in mammalian cells. Competent NHEJ catalyses repair of DSBs by joining together and ligating two free DNA ends of little homology (microhomology) or DNA ends of no homology. The core components of mammalian NHEJ are the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku subunits Ku70 and Ku80, Artemis, XRCC4 and DNA ligase IV. DNA-PK is a nuclear serine/threonine protein kinase that comprises a catalytic subunit (DNA-PKcs), with the Ku subunits acting as the regulatory element. It has been proposed that DNA-PK is a molecular sensor for DNA damage that enhances the signal via phosphorylation of many downstream targets. The crucial role of DNA-PK in the repair of DSBs is highlighted by the hypersensitivity of DNA-PK-/- mice to IR and the high levels of unrepaired DSBs after genotoxic insult. Recently, DNA-PK has emerged as a suitable genetic target for molecular therapeutics such as siRNA, antisense and novel inhibitory small molecules. This review encompasses the recent literature regarding the role of DNA-PK in the protection of genomic stability and focuses on how this knowledge has aided the development of specific DNA-PK inhibitors, via both small molecule and directed molecular targeting techniques. This review promotes the inhibition of DNA-PK as a valid approach to enhance the tumor-cell-killing effects of treatments such as IR.

Cyclins and cdks in development and cancer: a perspective

Abstract: A fundamental aspect of cancer is dysregulated cell cycle control. Unlike normal cells that only proliferate when compelled to do so by developmental or other mitogenic signals in response to tissue growth needs, the proliferation of cancer cells proceeds essentially unchecked. This does not mean that cancer cell cycles are necessarily different from those found in normal cycling cells, but rather implies that cancer cells proliferate because they are no longer subject to proliferation-inhibitory influences arising from the stroma or from gene expression pattern changes consequent to 'terminal' differentiation, nor do they necessarily require extrinsic growth factors to recruit them into or maintain their proliferative state. Finally, cancer cells have also often avoided normal controls linked to cell cycle progression that halt proliferation in the presence of damaged DNA or other physiological insults. The result of these alterations is the inappropriate proliferation commonly associated with cancerous tumor formation. This review will summarize the current understanding of dysregulation of the G0/G1-to-S-phase transition in cancer cells, with particular emphasis on recent in vivo studies that suggest a need to rethink existing models of cell cycle control in development and tumorigenesis.

PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP.

Abstract: Protein kinase B (PKB/Akt) has been shown to play a role in protection from apoptosis, cell proliferation and cell growth. It is also involved in mediating the effects of insulin, such as lipogenesis, glucose uptake and conversion of glucose into fatty acids and cholesterol. Sterol-regulatory element binding proteins (SREBPs) are the major transcription factors that regulate genes involved in fatty acid and cholesterol synthesis. It has been postulated that constitutive activation of the phosphatidylinositol 3 kinase/Akt pathway may be involved in fatty acid and cholesterol accumulation that has been described in several tumour types. In this study, we have analysed changes in gene expression in response to Akt activation using DNA microarrays. We identified several enzymes involved in fatty acid and cholesterol synthesis as targets for Akt-regulated transcription. Expression of these enzymes has previously been shown to be regulated by the SREBP family of transcription factors. Activation of Akt induces synthesis of full-length SREBP-1 and SREBP-2 proteins as well as expression of fatty acid synthase (FAS), the key regulatory enzyme in lipid biosynthesis. We also show that Akt leads to the accumulation of nuclear SREBP-1 but not SREBP-2, and that activation of SREBP is required for Akt-induced activation of the FAS promoter. Finally, activation of Akt induces an increase in the concentration of cellular fatty acids as well as phosphoglycerides, the components of cellular membranes. Our data indicate that activation of SREBP by Akt leads to the induction of key enzymes of the cholesterol and fatty acid biosynthesis pathways, and thus membrane lipid biosynthesis.

Polo-like kinases (Plks) and cancer.

Abstract: Deregulated centrosome duplication or maturation often results in increased centrosome size and/or centrosome number, both of which show a positive and significant correlation with aneuploidy and chromosomal instability, thus contributing to cancer formation. Given the role of Polo-like kinases (Plks) in the centrosome cycle, it is not unexpected that deregulated expression of Plks is detected in many types of cancer and is associated with oncogenesis. Extensive studies have shown that Plk1 expression is elevated in non-small-cell lung cancer, head and neck cancer, esophageal cancer, gastric cancer, melanomas, breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, gliomas, and thyroid cancer. Plk1 gene and protein expression has been proposed as a new prognostic marker for many types of malignancies, and Plk1 is a potential target for cancer therapy. In contrast to Plk1, several studies have observed that Plk3 expression is negatively correlated with the development of certain cancers.

Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis.

Abstract: Transforming growth factor-beta (TGF-beta) superfamily members signal via membrane-bound heteromeric serine-threonine kinase receptor complexes. Upon ligand-binding, receptor activation leads to phosphorylation of cytoplasmic protein substrates of the Smad family. Following phosphorylation and oligomerization, the latter move into the nucleus to act as transcription factors to regulate target gene expression. TGF-beta responses are not solely the result of the activation Smad cascade, but are highly cell-type specific and dependent upon interactions of Smad signaling with a variety of other intracellular signaling mechanisms, initiated or not by TGF-beta itself, that may either potentiate, synergize, or antagonize, the rather linear TGF-beta/Smad pathway. These include, (a), regulation of Smad activity by mitogen-activated protein kinases (MAPKs), (b), nuclear interaction of activated Smads with transcriptional cofactors, whether coactivators or corepressors, that may be themselves be regulated by diverse signaling mechanisms, and (c), negative feedback loops exerted by inhibitory Smads, transcriptional targets of the Smad cascade. This review focuses on how MAPKs modulate the outcome of Smad activation by TGF-beta, and how cross-signaling mechanisms between the Smad and MAPK pathways may take place and affect cell fate in the context of carcinogenesis.

Molecular mechanisms of cellular transformation by HTLV-1 Tax.

Abstract: The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.

The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer

Abstract: Wnt glycoproteins regulate homeostasis and development by binding to membrane Frizzled-LRP5/6 receptor complexes. Wnt signaling includes a canonical pathway involving cytosolic beta-catenin stabilization, nuclear translocation and gene regulation, acting as a co-activator of T-cell factor (TCF) proteins, and noncanonical pathways that activate Rho, Rac, JNK and PKC, or modulate Ca(2+) levels. DICKKOPF-1 (DKK-1) encodes a secreted Wnt antagonist that binds to LRP5/6 and induces its endocytosis, leading to inhibition of the canonical pathway. We show that activation of canonical signaling by Wnt1 or ectopic expression of active beta-catenin, TCF4 or LRP6 mutants induces transcription of the human DKK-1 gene. Multiple beta-catenin/TCF4 sites in the DKK-1 gene promoter contribute to this activation. In contrast, Wnt5a, which signals through noncanonical pathways, does not activate DKK-1. Northern and Western blot studies show that activation of the Wnt/beta-catenin pathway by treatment with lithium or Wnt3a-conditioned medium, or by stable expression of either Wnt1 or beta-catenin, increases DKK-1 RNA and protein, thus initiating a negative feedback loop. However, we found that DKK-1 expression decreases in human colon tumors, which suggests that DKK-1 acts as a tumor suppressor gene in this neoplasia. Our data indicate that the Wnt/beta-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer.

Polo-like kinases and oncogenesis

Abstract: Polo-like kinases (Plks) play pivotal roles in the regulation of cell cycle progression. Plk1, the best characterized family member among mammalian Plks, strongly promotes the progression of cells through mitosis. Furthermore, Plk1 is found to be overexpressed in a variety of human tumors and its expression correlates with cellular proliferation and prognosis of tumor patients. Although all Plks share two conserved elements, the N-terminal Ser/Thr kinase domain and a highly homologues C-terminal region termed the polo-box motif, their functions diverge considerably. While Plk1 is inhibited by different checkpoint pathways, Plk2 and Plk3 are activated by the spindle checkpoint or the DNA damage checkpoint. Thus, Plk2 and Plk3 seem to inhibit oncogenic transformation. Deregulation of Plk1 activity contributes to genetic instability, which in turn leads to oncogenic transformation. In contrast, Plk2 and Plk3 are involved in checkpoint-mediated cell cycle arrest to ensure genetic stability, thereby inhibiting the accumulation of genetic defects. In this review, we shall discuss the roles of Plks in oncogenesis and Plk1 as a target for therapeutic intervention against cancer.

Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3

Abstract: Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3

HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas

Abstract: Hypoxia stimulates a number of pathways critical to cancer cell survival, including the activation of vascular endothelial growth factor (VEGF) transcription. In normal fibroblasts, hypoxia-induced activation of the protein tyrosine kinase, Src, is required for VEGF expression. We show here in both pancreatic and prostate carcinoma cell lines cobalt chloride (used to mimic hypoxia) -induced VEGF expression requires Src activation and leads to increased steady-state levels of HIF-1alpha and increased phosphorylation of signal and transducer of transcription 3 (STAT3). STAT3 and hypoxia-inducible factor (HIF)-1alpha bind simultaneously to the VEGF promoter, where they form a molecular complex with the transcription coactivators CBP/p300 and Ref-1/APE. Expression of activated Src from an inducible promoter is sufficient to increase VEGF expression and form these STAT3/HIF-1alpha-containing promoter complexes. Inhibition of DNA binding by expression of either STAT3 or HIF-1alpha dominant negative mutants significantly reduces VEGF expression. These data suggest that the binding of both STAT3 and HIF-1alpha to the VEGF promoter is required for maximum transcription of VEGF mRNA following hypoxia.

Stat3 regulates genes common to both wound healing and cancer

Abstract: Wound healing and cancer are both characterized by cell proliferation, remodeling of extracellular matrix, cell invasion and migration, new blood vessel formation, and modulation of blood coagulation. The mechanisms that link wound healing and cancer are poorly understood. We report here that Stat3, a common signaling mechanism involved in oncogenesis and tissue injury, regulates a common set of genes involved in wound healing and cancer. Using oligonucleotide gene arrays and quantitative real-time PCR, we evaluated changes in global gene expression resulting from expression of Stat3 in lung epithelial cells. We report here previously uncharacterized genes induced by Stat3 implicated in signaling pathways common to both wound healing and cancer including cell invasion and migration, angiogenesis, modulation of coagulation, and repression of interferon-inducible genes. Consistent with these results, we found increased Stat3 activity associated with wound healing in chronically inflamed mouse lungs and increased Stat3 activity was identified at the leading edge of lung tumors invading adjacent nontumor stroma. These findings provide a molecular basis for understanding cancer as a deregulation of normal wound healing processes.