Research Interests:
Numerous biologic processes and such diseases as cancer depend on activation of tyrosine kinase receptors. The RET tyrosine kinase receptor was discovered two decades ago as a transforming gene and was subsequently implicated in the... more
Numerous biologic processes and such diseases as cancer depend on activation of tyrosine kinase receptors. The RET tyrosine kinase receptor was discovered two decades ago as a transforming gene and was subsequently implicated in the formation of papillary and medullary thyroid carcinoma. This article examines the data about the mechanism of activation of downstream signal transduction pathways by RET oncoproteins. Collectively, these findings have advanced the understanding of the processes underlying thyroid carcinoma formation.
Research Interests:
Research Interests:
Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of many malignancies. Many inhibitors targeting GRP signalling have been developed and tested as anticancer... more
Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of many malignancies. Many inhibitors targeting GRP signalling have been developed and tested as anticancer compounds showing promising preclinical and early phase clinical results. In this review we will discuss the molecular signalling, the expression and the functional role of BN/GRP-GRPR in different cancer models and will focus on the available strategies to target BN/GRP-GRPR in cancer treatment as well as in tumour diagnosis and follow up.
The hedgehog (Hh) signaling pathway, which is almost completely silenced in normal adult tissues but highly activated in cancer, offers ideal drug targets for small molecule development. During the last few years, several studies have... more
The hedgehog (Hh) signaling pathway, which is almost completely silenced in normal adult tissues but highly activated in cancer, offers ideal drug targets for small molecule development. During the last few years, several studies have indicated that the Hh pathway plays a role in tumor development and maintenance, and novel drugs inhibiting Hh signaling have been discovered. Although results from clinical trials in patients harboring activating mutations of Hh have been promising, there are many controversies regarding the role of the pathway in tumors that demonstrate ligand over-expression without identified mutations. In this review, we focus on the function and expression of the Hh pathway in different tumors and discuss the targeting approaches tested in preclinical and clinical studies.
Research Interests:
The RET tyrosine kinase is a functional receptor for neurotrophic ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Loss of function of RET is associated with congenital megacolon or Hirschsprung's disease,... more
The RET tyrosine kinase is a functional receptor for neurotrophic ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Loss of function of RET is associated with congenital megacolon or Hirschsprung's disease, whereas germ-line point mutations causing RET activation are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and familial medullary thyroid carcinoma) syndromes. Here we show that the expression of a constitutively active RET-MEN2A oncogene promotes survival of rat pheochromocytoma PC12 cells upon growth factor withdrawal. Moreover, we show that the RET-MEN2A-mediated survival depends on signals transduced by the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. Thus, in PC12 cells, RET-MEN2A associates with the PI3K regulatory subunit p85 and promotes activation of Akt (also referred to as protein kinase B) in a PI3K-dependent fashion; in addition, RET-MEN2A promotes MAPK activation. PI3K recruit...
Research Interests:
Research Interests:
Research Interests: Gene regulation, Cell Cycle, Cell Adhesion, Extracellular Matrix, Molecular Mechanics, and 16 moreSignal Transduction, Cell morphology, Mice, Animals, Oncogene, T cells, Protein Function, Clinical Sciences, Cdna Microarray, Hierarchical Cluster Analysis, Global Gene Expression, Rho GTPase, Gene Expression Regulation, Gene expression profiling, Cell Motility, and Cell Growth
NCOA4 is a transcriptional coactivator of nuclear hormone receptors that undergoes gene rearrangement in human cancer. By combining studies in Xenopus laevis egg extracts and mouse embryonic fibroblasts (MEFs), we show here that NCOA4 is... more
NCOA4 is a transcriptional coactivator of nuclear hormone receptors that undergoes gene rearrangement in human cancer. By combining studies in Xenopus laevis egg extracts and mouse embryonic fibroblasts (MEFs), we show here that NCOA4 is a minichromosome maintenance 7 (MCM7)-interacting protein that is able to control DNA replication. Depletion-reconstitution experiments in Xenopus laevis egg extracts indicate that NCOA4 acts as an inhibitor of DNA replication origin activation by regulating CMG (CDC45/MCM2-7/GINS) helicase. NCOA4(-/-) MEFs display unscheduled origin activation and reduced interorigin distance; this results in replication stress, as shown by the presence of fork stalling, reduction of fork speed, and premature senescence. Together, our findings indicate that NCOA4 acts as a regulator of DNA replication origins that helps prevent inappropriate DNA synthesis and replication stress.
Research Interests:
Research Interests:
Research Interests: MicroRNA, Apoptosis, Gene expression, Multidisciplinary, Signal Transduction, and 15 moreFree Radical, Cell line, Ischemia, Mice, Animals, Male, Signal Transduction Pathway Models, Phosphorylation, Superoxide Dismutase, Mitogen Activated Protein Kinase, PLoS one, Hydrogen Peroxide, Rats, Superoxide Anion, and Cell Survival
Research Interests: Cytokines, Inflammation, Macrophages, Transcription Factors, Signal Transduction, and 15 moreInflammatory Immune Response, Autoimmune Disease, Mutation, Thyroid gland, Mice, Animals, Oncogene, Cell Death, NF-kappa B, Clinical Sciences, Rats, Human Fibroblasts, Protein Binding, Fusion Protein, and Tyrosine Kinase
Research Interests: Membrane Proteins, DNA replication, Apoptosis, Signal Transduction, Cell line, and 18 moreHumans, Thyroid gland, Mice, Female, Animals, Oncogene, T cells, Phenotype, Clinical Sciences, Neoplasm Invasiveness, Rats, Transfection, Actin Filaments, Cell Survival, Adenocarcinoma, Dimerization, Tyrosine Kinase, and Stress fibers
Small cell lung carcinoma (SCLC) often features the upregulation of the Sonic hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells secrete bombesin (BBS)-like neuropeptides that act as autocrine growth... more
Small cell lung carcinoma (SCLC) often features the upregulation of the Sonic hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells secrete bombesin (BBS)-like neuropeptides that act as autocrine growth factors. Here, we show that SCLC tumor samples feature co-expression of Shh and BBS-cognate receptor (gastrin-releasing peptide receptor (GRPR)). We also demonstrate that BBS activates Gli in SCLC cells, which is crucial for BBS-mediated SCLC proliferation, because cyclopamine, an inhibitor of the Shh pathway, hampered the BBS-mediated effects. BBS binding to GRPR stimulated Gli through its downstream Gαq and Gα12/13 GTPases, and consistently, other Gαq and Gα13 coupled receptors (such as muscarinic receptor, m1, and thrombin receptor, PAR-1) and constitutively active GαqQL and Gα12/13QL mutants stimulated Gli. By using cells null for Gαq and Gα12/13, we demonstrate that these G proteins are strictly necessary for Gli activation by BBS. Moreover, by using constitutively active Rho small G-protein (Rho QL) as well as its inhibitor, C3 toxin, we show that Rho mediates G-protein-coupled receptor (GPCR)-, Gαq- and Gα12/13-dependent Gli stimulation. At the molecular level, BBS caused a significant increase in Shh gene transcription and protein secretion that was dependent on BBS-induced GPCR/Gαq-12/13/Rho mediated activation of nuclear factor κB (NFκB), which can stimulate a NF-κB response element in the Shh gene promoter. Our data identify a novel molecular network acting in SCLC linking autocrine BBS and Shh circuitries and suggest Shh inhibitors as novel therapeutic strategies against this aggressive cancer type.
Research Interests:
Some cancer types are strongly associated with chronic inflammatory or infectious diseases whereas others are not, but an inflammatory component is present in most human neoplastic lesions. This review focuses on various aspects of... more
Some cancer types are strongly associated with chronic inflammatory or infectious diseases whereas others are not, but an inflammatory component is present in most human neoplastic lesions. This review focuses on various aspects of thyroid cancer and inflammation. The incidence of thyroid cancer, in particular of well-differentiated papillary thyroid carcinomas (PTCs), is increased in autoimmune thyroid diseases such as Hashimoto's thyroiditis. Thyroid cancer often has an inflammatory cell infiltrate, which includes lymphocytes, macrophages, dendritic cells and mast cells, whose role in thyroid cancer is still not completely understood. However, most experimental evidence suggests these cells exert a protumorigenic function. Moreover, oncoproteins typically expressed in human PTCs, such as RET/PTC, RAS, and BRAF, trigger a proinflammatory programme in thyreocytes. These data suggest that inflammatory molecules are promising targets for thyroid cancer therapy.
Research Interests:
Inappropriate activation of the RET receptor tyrosine kinase causes development of papillary and medullary thyroid cancer. We have previously shown that pyrazolopyrimidine is a potent inhibitor of the RET kinase. Here, we show that... more
Inappropriate activation of the RET receptor tyrosine kinase causes development of papillary and medullary thyroid cancer. We have previously shown that pyrazolopyrimidine is a potent inhibitor of the RET kinase. Here, we show that 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) (PP2), another pyrazolopyrimidine, blocks the enzymatic activity of the isolated RET kinase and RET/PTC1 oncoprotein at IC(50) in the nanomolar range. PP2 blocked in vivo phosphorylation and signaling of the RET/PTC1 oncoprotein. PP2 prevented serum-independent growth of RET/PTC1-transformed NIH3T3 fibroblasts and of TPC1 and FB2, two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements. Finally, PP2 blocked invasion of type I collagen matrix by TPC1 cells. Thus, pyrazolopirimidines hold promise for the treatment of human cancers sustaining oncogenic activation of RET.
Research Interests:
The alpha-subunit of G proteins of the G(12/13) family stimulate Rho by their direct binding to the RGS-like (RGL) domain of a family of Rho guanine nucleotide exchange factors (RGL-RhoGEFs) that includes PDZ-RhoGEF (PRG), p115RhoGEF, and... more
The alpha-subunit of G proteins of the G(12/13) family stimulate Rho by their direct binding to the RGS-like (RGL) domain of a family of Rho guanine nucleotide exchange factors (RGL-RhoGEFs) that includes PDZ-RhoGEF (PRG), p115RhoGEF, and LARG, thereby regulating cellular functions as diverse as shape and movement, gene expression, and normal and aberrant cell growth. The structural features determining the ability of G alpha(12/13) to bind RGL domains and the mechanism by which this association results in the activation of RGL-RhoGEFs are still poorly understood. Here, we explored the structural requirements for the functional interaction between G alpha(13) and RGL-RhoGEFs based on the structure of RGL domains and their similarity with the area by which RGS4 binds the switch region of G alpha(i) proteins. Using G alpha(i2), which does not bind RGL domains, as the backbone in which G alpha(13) sequences were swapped or mutated, we observed that the switch region of G alpha(13) is strictly necessary to bind PRG, and specific residues were identified that are critical for this association, likely by contributing to the binding surface. Surprisingly, the switch region of G alpha(13) was not sufficient to bind RGL domains, but instead most of its GTPase domain is required. Furthermore, membrane localization of G alpha(13) and chimeric G alpha(i2) proteins was also necessary for Rho activation. These findings revealed the structural features by which G alpha(13) interacts with RGL domains and suggest that molecular interactions occurring at the level of the plasma membrane are required for the functional activation of the RGL-containing family of RhoGEFs.
Research Interests:
CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential... more
CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease- and γ-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD44-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAF oncogenes exhibited CD44 cleavage and CD44-ICD accumulation. Chemical blockade of RET/PTC, BRAF, metalloprotease, or γ-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of γ-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma.
Research Interests:
Colorectal cancer poses a major clinical challenge in the developed world where this disease is common. Recent findings suggest that the prostaglandin E(2), the proinflammatory product of elevated cyclooxygenase-2 activity in colon... more
Colorectal cancer poses a major clinical challenge in the developed world where this disease is common. Recent findings suggest that the prostaglandin E(2), the proinflammatory product of elevated cyclooxygenase-2 activity in colon cancer, stimulates cancer cell growth through a G protein-dependent signaling pathway coupling the prostaglandin EP2 receptor to beta-catenin control. These findings provide new insights into the molecular framework needed to evaluate chemopreventive strategies for colorectal cancer.
Research Interests:
Research Interests:
Thyroid cancer is frequently associated with the oncogenic conversion of receptor tyrosine kinases (RTKs) or their downstream signalling molecules. Hence, there is a strong biological rationale for assessing the efficacy of RTK blockade... more
Thyroid cancer is frequently associated with the oncogenic conversion of receptor tyrosine kinases (RTKs) or their downstream signalling molecules. Hence, there is a strong biological rationale for assessing the efficacy of RTK blockade to treat patients who are resistant to or not candidates for treatment with radioactive iodine. The first results of clinical trials based on the use of RTK inhibitors in thyroid cancer patients have recently been published. Here we discuss targeting of specific RTKs as a potential therapeutic strategy for the treatment of thyroid cancer.