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At least 433 records · Page 24Linked to original sources
PubMed2004

The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae.

When faced with nutrient deprivation, Saccharomyces cerevisiae cells enter into a nondividing resting state, known as stationary phase. The Ras/PKA (cAMP-dependent protein kinase) signaling pathway plays an important role in regulating the entry into this resting state and the subsequent survival of stationary phase cells. The survival of these resting cells is also dependent upon autophagy, a membrane trafficking pathway that is induced upon nutrient deprivation. Autophagy is responsible for targeting bulk protein and other cytoplasmic constituents to the vacuolar compartment for their ultimate degradation. The data presented here demonstrate that the Ras/PKA signaling pathway inhibits an early step in autophagy because mutants with elevated levels of Ras/PKA activity fail to accumulate transport intermediates normally associated with this process. Quantitative assays indicate that these increased levels of Ras/PKA signaling activity result in an essentially complete block to autophagy. Interestingly, Ras/PKA activity also inhibited a related process, the cytoplasm to vacuole targeting (Cvt) pathway that is responsible for the delivery of a subset of vacuolar proteins in growing cells. These data therefore indicate that the Ras/PKA signaling pathway is not regulating a switch between the autophagy and Cvt modes of transport. Instead, it is more likely that this signaling pathway is controlling an activity that is required during the early stages of both of these membrane trafficking pathways. Finally, the data suggest that at least a portion of the Ras/PKA effects on stationary phase survival are the result of the regulation of autophagy activity by this signaling pathway.

Autophagy↗
PubMed2004

Comparison of TGF-beta/BMP pathways signaled by demineralized bone powder and BMP-2 in human dermal fibroblasts.

UNLABELLED: Demineralized bone induces chondrogenic differentiation of human dermal fibroblasts in vitro. Analyses of signaling gene expression showed that DBP and BMP-2 regulate common and distinct pathways. Although BMP-2 was originally isolated as a putative active factor in DBP, rhBMP-2 and DBP do not affect all the same genes or in the same ways. INTRODUCTION: Demineralized bone powder (DBP) induces chondrogenic differentiation of human dermal fibroblasts (hDFs) in 3D culture, but the initiating mechanisms have not been identified. We tested the hypotheses that DBP would affect expression of signaling genes and that DBP's effects would differ from the effects of bone morphogenetic proteins (BMPs). MATERIALS AND METHODS: A chondroinduction model was used in which hDFs were cultured with and without DBP in a porous collagen sponge. BMP-2 was delivered in a square of absorbable collagen felt inserted into a collagen sponge. Total RNA was isolated after 3 days of culture, a time that precedes expression of the chondrocyte phenotype. Gene expression was evaluated with two targeted macroarray screens. Effects of DBP and rhBMP-2 were compared by macroarray, RT-PCR, and Northern hybridization analysis of selected genes in the transforming growth factor (TGF)-beta/BMP signaling pathways. RESULTS: By macroarray analysis of 16 signal transduction pathways, the following pathways were modulated in hDFs by DBP: TGF-beta, insulin/LDL, hedgehog, PI3 kinase/AKT, NF-kappaB, androgen, retinoic acid, and NFAT. There was convergence and divergence in DBP and rhBMP-2 regulation of genes in the TGF-beta/BMP signaling pathway. Smad target genes were the predominant group of DBP- or rhBMP-2-regulated genes. Several genes (IGF-BP3, ID2, and ID3) showed similar responses (increased expression) to DBP and rhBMP-2. In contrast, many of the genes that were greatly upregulated by DBP (TGFBI/betaig-h3, Col3A1, TIMP1, p21/Waf1/Cip1) were barely affected by rhBMP-2. CONCLUSION: These findings indicate that multiple signaling pathways are regulated in fibroblasts by DBP, that one of the major pathways involves Smad target genes, and that DBP and rhBMP-2 elicit different gene expression responses in hDFs. Although BMP-2 was originally isolated as a putative inductive factor in DBP, rhBMP-2 and DBP do not affect all the same genes or in the same ways.

Animals↗
PubMed1999

Crosstalk between protein kinase A and growth factor receptor signaling pathways in arterial smooth muscle.

Crosstalk between the cyclic AMP-dependent protein kinase (PKA) and growth factor receptor signaling is one of many emerging concepts of crosstalk in signal transduction. Understanding of PKA crosstalk may have important implications for studies of crosstalk between other, less well known, signaling pathways. This review focuses on PKA crosstalk in arterial smooth muscle. Proliferation and migration of arterial smooth muscle cells (SMCs) contribute to the thickening of the blood vessel wall that occurs in many types of cardiovascular disease. PKA potently inhibits SMC proliferation by antagonizing the major mitogenic signaling pathways induced by growth factors in SMCs. PKA also inhibits growth factor-induced SMC migration. An intricate crosstalk between PKA and the mitogen-activated protein kinase (MAPK/ERK) pathway, the p70 S6 kinase pathway and cyclin-dependent kinases has been described. Further, PKA regulates expression of growth regulatory molecules. The result of PKA activation in SMCs is the potent inhibition of cell cycle traverse and SMC migration. In this review, we discuss recent advances in our understanding of the crosstalk between PKA and signaling pathways induced by growth factor receptors in SMCs, and where relevant, in other cell types in which interesting examples of PKA crosstalk have been described.

Animals↗
PubMed2001

No evidence of deregulated patched-hedgehog signaling pathway in trichoblastomas and other tumors arising within nevus sebaceous.

Nevus sebaceous is a congenital malformation of the skin within which a number of neoplasms showing adnexal differentiation may arise. Recently, deletions in the patched gene region were reported in nevus sebaceous and constitutive activation of the patched-hedgehog signaling pathway was implicated in the development of tumors arising within nevus sebaceous. To substantiate further a role of the patched-hedgehog signaling pathway in secondary tumors arising within nevus sebaceous, we examined 11 nevus sebaceous associated with secondary tumors for loss of heterozygosity of the patched gene region by microsatellite polymerase chain reaction and patched mRNA expression by in situ hybridization. Unexpectedly, however, none of the tumors (including eight trichoblastomas) and nevus sebaceous lesions showed loss of heterozygosity at any polymorphic loci close to the patched gene. Further more, none of the nevus sebaceous lesions and secondary tumors gave detectable signals for patched mRNA. In contrast, four of 11 sporadic basal cell carcinomas, that were examined for comparison, showed loss of heterozygosity at the patched gene locus (p <0.05), and moderate to strong signals for patched mRNA was observed in all seven basal cell carcinoma tumors examined (p <0.0001). Additional investigation by reverse transcription-polymerase chain reaction in four basal cell carcinomas and two nevus sebaceous tumors also showed the expression of Gli-1, another target gene in the patched-hedgehog signaling pathway, in all the basal cell carcinomas samples but not in any of the nevus sebaceous tumors examined. The findings in this study do not support the view that the deregulation of the patched-hedgehog signaling pathway is involved in the pathogenesis of nevus sebaceous and associated tumors, and show that, although morphologically similar, trichoblastomas and basal cell carcinomas have a different molecular pathogenesis.

Adult↗
PubMed1999

The role of phosphatidylinositol 3-kinase, Src kinase, and protein kinase A signaling pathways in insulin and glucagon regulation of CYP2E1 expression.

The signaling pathways involved in insulin and glucagon regulation of CYP2E1 expression were examined in primary cultured rat hepatocytes. Insulin addition to primary cultured rat hepatocytes for 24 h resulted in an approximately 80% and >90% decrease in CYP2E1 mRNA levels at 1 and 10 nM insulin, respectively, relative to untreated cells. Addition of the phosphatidylinositol 3-kinase inhibitor wortmannin, or the Src kinase inhibitor geldanamycin, prior to insulin addition, inhibited the insulin-mediated decline in CYP2E1 mRNA. In contrast, treatment of cells with glucagon (100 nM), or the cAMP analogue dibutyryl-cAMP (50 microM), for 24 h increased CYP2E1 mRNA levels by approximately 7-fold. Addition of the protein kinase A inhibitor H89 prior to glucagon treatment attenuated the glucagon-mediated increase in CYP2E1 mRNA by approximately 70%. Glucagon (100 nM) opposed the effects of insulin (1 nM) on CYP2E1 mRNA expression and conversely, insulin blocked the effects of glucagon. These data provide compelling evidence for the regulation of CYP2E1 expression via mutually antagonistic signaling pathways involving insulin and glucagon.

Androstadienes↗
PubMed2003

Exploring potential target genes of signaling pathways by predicting conserved transcription factor binding sites.

Many cellular signaling pathways induce gene expression by activating specific transcription factor complexes. Conventional approaches to the prediction of transcription factor binding sites lead to a notoriously high number of false discoveries. To alleviate this problem, we consider only binding sites that are conserved in man-mouse genomic sequence comparisons. We employ two alternative methods for predicting binding sites: exact matches to validated binding site sequences and weight matrix scans. We then ask the question whether there is a characteristic association between a transcription factor or set thereof to a particular group of genes. Our approach is tested on genes, which are induced in dendritic cells in response to the cells' exposure to LPS. We chose this example because the underlying signaling pathways are well understood. We demonstrate the benefit of conserved predicted binding sites in interpreting the LPS experiment. Additionally, we find that both methods for the prediction of conserved binding sites complement one another. Finally, our results suggest a distinct role for SRF in the context of LPS-induced gene expression.

Algorithms↗
PubMed2004

Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.

Adipose Tissue↗
PubMed2004

Downregulation of the growth hormone-induced Janus kinase 2/signal transducer and activator of transcription 5 signaling pathway requires an intact actin cytoskeleton.

Transient activation of the signal transducers and activators of transcription (STAT) proteins in response to growth hormone (GH) and other type II cytokines plays a pivotal role on specific gene transcription. The negative regulation of STATs seems to be exerted at the GH receptor (GHR)/Janus Kinase (JAK) complex and involves two main mechanisms: (1) the GH-induced ubiquitination/internalization of GHR and (2) the action of SOCS proteins. Since GH regulates cellular cytoskeleton with potential implications in GH signaling, we investigated the effects of actin cytoskeleton disruption on the kinetics of GH-activated GHR/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling pathway. Disruption of the actin-based cytoskeleton with cytochalasin D (CytoD) did not affect the rapid GH induction of JAK2 and STAT5 activities. However, pretreatment of BRL-4 cells with CytoD prolonged both, JAK2/STAT5 tyrosine phosphorylation and STAT5 DNA binding activity, for at least 2 h. Our results demonstrated that the synthesis of the several SOCS proteins (SOCS-1, -2, and -3) was not affected by treatment of the cells with CytoD. On the other hand, the inhibitory actions of SOCS1, 2, and -3 on GH-induced STAT5 reporter activity were partially blocked by disruption of the cytoskeleton. Disassembly of the actin filaments by CytoD is accompanied by accumulation of ubiquitinated forms of GHR but it does not affect GHR internalization. We conclude that the integrity of the actin cytoskeleton network plays an essential role in the negative regulation of GHR/JAK2/STAT5 signaling pathway by facilitating the GHR ubiquitination/degradation through mechanisms acting downstream SOCS.

Actin Cytoskeleton↗
PubMed2005

Ryanodine receptor subtype 2 encodes Ca2+ oscillations activated by acetylcholine via the M2 muscarinic receptor/cADP-ribose signalling pathway in duodenum myocytes.

In this study, we characterized the signalling pathway activated by acetylcholine that encodes Ca2+ oscillations in rat duodenum myocytes. These oscillations were observed in intact myocytes after removal of external Ca2+, in permeabilized cells after abolition of the membrane potential and in the presence of heparin (an inhibitor of inositol 1,4,5-trisphosphate receptors) but were inhibited by ryanodine, indicating that they are dependent on Ca2+ release from intracellular stores through ryanodine receptors. Ca2+ oscillations were selectively inhibited by methoctramine (a M2 muscarinic receptor antagonist). The M2 muscarinic receptor-activated Ca2+ oscillations were inhibited by 8-bromo cyclic adenosine diphosphoribose and inhibitors of adenosine diphosphoribosyl cyclase (ZnCl2 and anti-CD38 antibody). Stimulation of ADP-ribosyl cyclase activity by acetylcholine was evaluated in permeabilized cells by measuring the production of cyclic guanosine diphosphoribose (a fluorescent compound), which resulted from the cyclization of nicotinamide guanine dinucleotide. As duodenum myocytes expressed the three subtypes of ryanodine receptors, an antisense strategy revealed that the ryanodine receptor subtype 2 alone was required to initiate the Ca2+ oscillations induced by acetylcholine and also by cyclic adenosine diphosphoribose and rapamycin (a compound that induced uncoupling between 12/12.6 kDa FK506-binding proteins and ryanodine receptors). Inhibition of cyclic adenosine diphosphoribose-induced Ca2+ oscillations, after rapamycin treatment, confirmed that both compounds interacted with the ryanodine receptor subtype 2. Our findings show for the first time that the M2 muscarinic receptor activation triggered Ca2+ oscillations in duodenum myocytes by activation of the cyclic adenosine diphosphoribose/FK506-binding protein/ryanodine receptor subtype 2 signalling pathway.

ADP-ribosyl Cyclase↗
PubMed1994

Coexistence of three tachykinin receptors coupled to Ca++ signaling pathways in intestinal muscle cells.

Receptors for tachykinins and the signaling pathway to which they are coupled were characterized in dispersed muscle cells from the longitudinal muscle layer of the rat intestine. A technique of receptor protection whereby selective agonists and antagonists were used to protect one receptor while other receptors were inactivated with N-ethylmaleimide enabled each tachykinin receptor type to be identified separately. Protection of neurokinin (NK)-1 receptors with the selective NK-1 agonist, substance P methylester, or antagonist, GR-82,334 (Glp-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-D-Pro[spiro-gamma-lactam]Leu-Trp-NH2), preserved the contractile response and increase in cytosolic-free Ca++ ([Ca++]i) induced by substance P methylester only; protection of NK-2 receptors with the selective NK-2 agonist, beta-[Ala8]NKA(4-10), or the selective NK-2b antagonist, L-659,877 [cyclo(Leu-Met-Gln-Trp-Phe-Gly)], preserved the contractile response and increase in [Ca++]i induced by beta-[Ala8]NKA(4-10) only; and protection of NK-3 receptors with the selective NK-3 agonist, senktide succinyl-[Asp6,MePhe8]substance P(6-11), preserved the contractile response and increase in [Ca++]i induced by succinyl-[Asp6,MePhe8]substance P(6-11) only. When used as a protective agent, the NK-2a antagonist, MEN-10,376 (H-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2), did not preserve the response to any tachykinin agonist. Protection of NK-1, NK-2 and NK-3 receptors preserved fully the responses to the preferential endogenous agonists, substance P, NKA and NKB, respectively, but they also preserved in part (30-40%) the responses to the nonpreferential agonists. Because substance P and NKA are coreleased from the same precursor in intestinal muscle tissue, the pattern implied the existence of considerable spareness in the contractile response of muscle cells to tachykinins. Studies on dispersed circular muscle cells using selective tachykinin agonists as protective agents confirmed the presence of three tachykinin receptor types. The results demonstrate the coexistence of NK-1, NK-2b and NK-3 receptors on muscle cells of rat intestine that are preferentially activated by substance P, NKA and NKB, respectively, and are coupled separately to one signaling pathway mediating contraction.

Amino Acid Sequence↗
PubMed1998

Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level.

BACKGROUND: The Wnt/Wingless signalling pathway plays an important role in both embryonic development and tumorigenesis. Beta-catenin and Axin are positive and negative effectors of the Wnt signalling pathway, respectively. RESULTS: We found that Axin interacts with beta-catenin and glycogen synthase kinase-3beta (GSK-3beta). Furthermore, the regulation of the G-protein signalling (RGS) domain of Axin is associated with the colorectal tumour suppressor adenomatous polyposis coli (APC). Overexpression of Axin in the human colorectal cancer cell line SW480 induced a drastic reduction in the level of -catenin. Interaction with beta-catenin and GSK-3beta was required for the Axin-mediated beta-catenin reduction. CONCLUSION: Axin interacts with beta-catenin, GSK-3beta and APC, and negatively regulates the Wnt signalling pathway, presumably by regulating the level of beta-catenin.

Adenomatous Polyposis Coli Protein↗
PubMed2001

Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways.

Genetic evidence that Toll-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor and biochemical evidence that Tlr4 confers LPS responsiveness as determined by activation of NF-kappaB and expression of inducible cyclooxygenase 2 have been demonstrated. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. It is now demonstrated that SFAs, but not unsaturated fatty acids (UFAs), induce NF-kappaB activation and expression of COX-2 and other inflammatory markers in macrophages. UFAs inhibit COX-2 expression induced by SFAs and LPS. Additional evidence suggests that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Whether fatty acids also modulate signaling pathways and target gene expression derived from the activation of other Tlrs remains to be determined.-Hwang, D. Modulation of the expression of cyclooxygenase 2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways.

Animals↗
PubMed2002

The phosphatidylinositol 3-kinase/Akt signaling pathway modulates the endocrine differentiation of trophoblast cells.

Activation of Lyn, a Src-related nonreceptor tyrosine kinase, in trophoblast cells is associated with trophoblast giant cell differentiation. The purpose of the present work was to use Lyn as a tool to identify signaling pathways regulating the endocrine differentiation of trophoblast cells. The Src homology 3 domain of Lyn was shown to display differentiation-dependent associations with other regulatory proteins, including phosphatidylinositol 3-kinase (PI3-K). PI3-K activation was dependent upon trophoblast giant cell differentiation. The downstream mediator of PI3-K, Akt/protein kinase B, also exhibited differentiation-dependent activation. Lyn is a potential regulator of the PI3-K/Akt signaling pathway, as are receptor tyrosine kinases. Protein tyrosine kinase profiling was used to identify two candidate regulators of the PI3-K/Akt pathway, fibroblast growth factor receptor-1 and Sky. At least part of the activation of Akt in differentiating trophoblast giant cells involves an autocrine growth arrest-specific-6-Sky signaling pathway. Inhibition of PI3-K activities via treatment with LY294002 disrupted Akt activation and interfered with the endocrine differentiation of trophoblast giant cells. In summary, activation of the PI3-K/Akt signaling pathway regulates the development of the differentiated trophoblast giant cell phenotype.

Animals↗
PubMed1996

Intracellular signaling pathways involved in the induction of apoptosis in immature thymic T lymphocytes.

We describe a novel technique for studying the signaling pathways that control thymocyte negative selection which maintains the essential interactions between thymocytes and thymic stromal cells. Bisected lobes from newborn mouse thymus are maintained in organ culture for up to 36 h, and the thymocytes analyzed by flow cytometry. Inclusion of [3H]inositol during culture allows measurements of phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) hydrolysis and inositol phosphate accumulation. Using this technique we have compared the thymocyte responses induced by anti-CD3, anti-Fas, Con A, and beta-adrenergic stimulation. We show that PtdIns(4,5)P2 hydrolysis precedes anti-CD3-induced thymocyte apoptosis, but not the apoptosis induced by anti-Fas. In contrast, Con A stimulates PtdIns(4,5)P2 hydrolysis, but does not induce thymocyte apoptosis. Anti-CD3, anti-Fas, and Con A all fail to change thymic cAMP levels, but beta-adrenergic stimulation causes a large increase in intracellular cAMP, and agents that elevate cAMP induce thymocyte apoptosis. Inhibition of protein synthesis (with cycloheximide or emetine) prevents the apoptosis induced by anti-CD3 and elevated cAMP, but not that induced by anti-Fas, whereas protease inhibition (with 3,4-dichloroisocoumarin or N(alpha)-tosyl-phenylalanine chloromethyl ketone) prevents the apoptosis caused by all of the effective stimuli. These results offer three important conclusions. First, activation of a variety of different signaling pathways can bring about thymocyte apoptosis. Second, ligation of the thymocyte TCR/CD3 complex provokes PtdIns(4,5)P2 hydrolysis, but signaling through this pathway alone does not necessarily lead to apoptosis. Third, by whichever signaling pathway the response is initiated, the activity of one or more protease enzymes appears to form an essential component in the final common pathway leading to apoptosis.

Adrenergic beta-Agonists↗
PubMed2005

Modulation of the steroidogenic activity of luteinizing hormone by insulin and insulin-like growth factor-I through interaction with the cAMP-dependent protein kinase signaling pathway in the trout ovary.

In the salmonid ovary, luteinizing hormone (LH) is the major gonadotropic hormone stimulating the production of steroids during the periovulatory period and its effects are mediated by the cAMP-dependent protein kinase (PKA) signaling pathway. We have previously shown that the in vitro steroidogenic activity of LH in the salmonid ovary is inhibited by insulin-like growth factor I (IGF-I) which, like insulin, has specific receptors in both theca and granulosa layers. In the present study, we have investigated the modulatory effects of insulin on salmon LH (sLH)-stimulated steroid production in preovulatory theca layers of brown trout (Salmo trutta) and the effects of both insulin and IGF-I on the sLH-stimulated cAMP/PKA signaling pathway. Our results show that insulin, like IGF-I, blocked the stimulatory effects of sLH, dibutyryl cAMP and IBMX on testosterone (T) production but not those of sLH on cAMP production. Furthermore, insulin and IGF-I blocked the activation of PKA induced by sLH and these effects were correlated with changes in the total protein content of the catalytic (C) and type II regulatory (RII) subunits of PKA. Interestingly, insulin and IGF-I had different effects on total PKA subunit content since insulin potentiated the sLH-stimulated increase in RII subunit content whereas IGF-I blocked the sLH-stimulated increase in total C subunit content. The effects of insulin and IGF-I in trout theca layers appeared to be mediated by the mitogen-activated protein kinase (MAPK) signaling pathway because inhibition of extracellular signal-regulated kinase 1/2(ERK1/2) activity completely blocked the inhibitory effects of insulin and IGF-I on the sLH-stimulated production of T and because insulin and IGF-I increased the total protein content of ERK1/2 in trout theca layers. Therefore, our results suggest that insulin and IGF-I, probably through the MAPK pathway, block the action of sLH in trout theca layers by modulating the cAMP/PKA signaling pathway.

1-Methyl-3-isobutylxanthine↗
PubMed2003

[Wnt/Frizzled signaling pathway in renal carcinoma].

OBJECTIVE: To investigate the transduction of Wnt/Frizzled signaling pathway, especially the function of T cell factor 4 (TCF(4)), in renal carcinoma. METHODS: A renal carcinoma yeast two hybrid library and a human TCF(4) yeast two hybrid expression vector were constructed. Proteins interacting with the bait protein human TCF(4) were obtained from the renal carcinoma yeast two hybrid library by reverse yeast two hybrid system. RESULTS: 67 positive clones interacting with the bait protein TCF(4) were obtained by reverse yeast two hybrid system, including 18 beta-catenin clones, 24 TCF(4) clones and 25 unknown clones. CONCLUSION: Wnt/Frizzled signaling pathway exists in renal carcinoma. TCF(4), its important signal factor, interacts with beta-catenin and forms homodimer or homocopolymer by itself, thus displaying its constitutive transcriptional activity.

Adenocarcinoma, Clear Cell↗
PubMed2006

Profiling signalling pathways of the receptor activator of NF-kappaB ligand-induced osteoclast formation in mouse monocyte cells, RAW264.7.

Cell-based signal chemical genomics can profile the signalling pathway for certain cellular events by using a target-known chemical library. To ascertain its usefulness, the receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis in mouse monocyte/macrophage cells RAW264.7 was used as an in vitro experimental model. Of 180 target-known inhibitors/activators formatted in a 384-well plate, 8 chemicals were shown to inhibit the osteoclast formation, but 4 chemicals enhanced this process. A variety of references support, or possibly lead one to expect the effects of these 12 chemicals on the cellular process of osteoclastogenesis in RAW264.7 cells, but several signalling pathways were newly found in this study; for example, CA-074 Me inhibiting cathepsin B and nitrendipine blocking the calcium channel could have the potential to inhibit the osteoclast formation as well as bone resorption. This is a simple but very fast and powerful method of profiling the signalling pathway of certain cellular events. Signal chemical genomics could provide invaluable information for the exploration of new target signalling processes and further target-based drug discovery strategies.

Acid Phosphatase↗
PubMed2006

Inhibition of SHH signaling pathway: molecular treatment strategy of odontogenic keratocyst.

Odontogenic keratocyst (OKC) is a relatively common cystic lesion occurred in the tooth-bearing areas of the jaws. This entity is thought to arise from the dental lamina or its remnant with significant growth capacity and recurrence potential. The Sonic hedgehog (SHH) signaling pathway plays a critical role in tooth development. Patched (PTCH) combines with Smoothened (SMO) to form a receptor complex for SHH ligand. Mutations in the PTCH resulting in aberrant activation of SHH signaling pathway were identified as the underlying genetic event of both sporadic and syndrome-related OKCs. We postulate that any strategy to develop antagonists of active receptor, transcriptional factors of SHH signaling pathway will be an effective treatment for OKC. These strategies include reintroducing a wild-type form of PTCH, inhibition of the SMO molecule by synthetic small antagonists and suppression of the downstream transcription factors of the SHH signaling pathway. It seems that inhibition of SMO by intracystic injection of antagonist protein of SMO is the most potential treatment choice.

Basal Cell Carcinoma↗