The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention.


:Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.






Renziehausen A,Wang H,Rao B,Weir L,Nigro CL,Lattanzio L,Merlano M,Vega-Rioja A,Del Carmen Fernandez-Carranco M,Hajji N,Matin R,Harwood C,Li S,Sim VR,O'Neill K,Evans A,Thompson A,Szlosarek P,Fleming C,Stebbing J,Pr




Has Abstract


2019-03-01 00:00:00
















  • tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors.

    abstract::A search for protein tyrosine kinases expressed during murine cardiogenesis resulted in the isolation of a novel tyrosine kinase, designated tek, which maps to mouse chromosome 4 between the brown and pmv-23 loci. The deduced amino acid sequence of tek predicts that it encodes a putative receptor tyrosine kinase that ...


    pub_type: 杂志文章


    authors: Dumont DJ,Yamaguchi TP,Conlon RA,Rossant J,Breitman ML

    更新日期:1992-08-01 00:00:00

  • FOXA1 inhibits prostate cancer neuroendocrine differentiation.

    abstract::Neuroendocrine prostate cancer (NEPC) has increasingly become a clinical challenge. The mechanisms by which neuroendocrine (NE) cells arises from prostate adenocarcinoma cells are poorly understood. FOXA1 is a transcription factor of the forkhead family that is required for prostate epithelial differentiation. In this...


    pub_type: 杂志文章


    authors: Kim J,Jin H,Zhao JC,Yang YA,Li Y,Yang X,Dong X,Yu J

    更新日期:2017-07-13 00:00:00

  • Mel-CAM-specific genetic suppressor elements inhibit melanoma growth and invasion through loss of gap junctional communication.

    abstract::Normal human melanocytes are interspersed singly among keratinocytes along the basement membrane of the epidermis, whereas melanoma cells readily adhere to each other during invasion of the dermis or distant organs. The tumorigenic and metastatic phenotype of melanoma cells often correlates with increased expression o...


    pub_type: 杂志文章


    authors: Satyamoorthy K,Muyrers J,Meier F,Patel D,Herlyn M

    更新日期:2001-08-02 00:00:00

  • The cyclin-dependent kinase inhibitor p27Kip1 is localized to the cytosol in Swiss/3T3 cells.

    abstract::p27Kip1 plays an important role in cell cycle progression by negatively regulating the activity of cyclin-Cdk complexes. To understand how p27Kip1 functions, the level and subcellular location of p27Kip1 in Swiss/3T3 cells following serum stimulation of quiescent cells was examined. Surprisingly, p27Kip1 was observed ...


    pub_type: 杂志文章


    authors: Wang G,Miskimins R,Miskimins WK

    更新日期:1999-09-16 00:00:00

  • Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer.

    abstract::D-type cyclins are important cell cycle regulators that promote cellular proliferation in response to growth factors by inactivation of the retinoblastoma protein (Rb). Cyclin D1 has been shown to be overexpressed in several cancer types and to act as an oncogene in breast cancers. As D-type cyclins are rate limiting ...


    pub_type: 杂志文章


    authors: Russell A,Thompson MA,Hendley J,Trute L,Armes J,Germain D

    更新日期:1999-03-18 00:00:00

  • Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571.

    abstract::Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit. In order to arrive at potentially new and novel therapy for SCLC, we have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines....


    pub_type: 杂志文章


    authors: Wang WL,Healy ME,Sattler M,Verma S,Lin J,Maulik G,Stiles CD,Griffin JD,Johnson BE,Salgia R

    更新日期:2000-07-20 00:00:00

  • A small compound targeting TACC3 revealed its different spatiotemporal contributions for spindle assembly in cancer cells.

    abstract::The mitotic spindle is assembled by the coordinated action of centrosomes and kinetochore microtubules. An evolutionally conserved protein family, transforming acidic coiled-coil (TACC), has been shown to be involved in this process. In humans, TACC3 is aberrantly expressed in a variety of human cancers, but its biolo...


    pub_type: 杂志文章


    authors: Yao R,Kondoh Y,Natsume Y,Yamanaka H,Inoue M,Toki H,Takagi R,Shimizu T,Yamori T,Osada H,Noda T

    更新日期:2014-08-14 00:00:00

  • CCND1 polymorphism and age of onset of hepatoblastoma.

    abstract::Cyclin D1, encoded by the gene CCND1, is a major regulator of the cell cycle transition from G1 phase to S phase. A CCND1 polymorphism (G to A) at codon 242, the boundary of exon 4 and intron 4, affects splicing such that exon 5 is not expressed in the A allele. Since exon 5 is involved in rapid turnover, the variant ...


    pub_type: 杂志文章


    authors: Pakakasama S,Chen TT,Frawley W,Muller CY,Douglass EC,Lee R,Pollock BH,Tomlinson GE

    更新日期:2004-06-10 00:00:00

  • LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs.

    abstract::LIM-kinase 2 (LIMK2) belongs to the LIMK family of proteins, which comprises LIMK1 and LIMK2. Both proteins regulate actin polymerization through phosphorylation and inactivation of the actin depolymerizing factor cofilin. In this study, we show that the level of LIMK2 protein is increased in neuroblastoma, BE(2)-C ce...


    pub_type: 杂志文章


    authors: Po'uha ST,Shum MS,Goebel A,Bernard O,Kavallaris M

    更新日期:2010-01-28 00:00:00

  • Patterns of expression of chromosome 17 genes in primary cultures of normal ovarian surface epithelia and epithelial ovarian cancer cell lines.

    abstract::Oligonucleotide microarray analysis was applied to assess the expression profile of 332 probe sets representing 308 genes or expressed sequence tags (ESTs) that map to chromosome 17 in order to address epigenetic events that result in alterations in gene expression in epithelial ovarian cancer (EOC). Expression profil...


    pub_type: 杂志文章


    authors: Presneau N,Mes-Masson AM,Ge B,Provencher D,Hudson TJ,Tonin PN

    更新日期:2003-03-13 00:00:00

  • Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells.

    abstract::Melanoma cells driven by mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) are highly resistant to chemotherapeutic treatments. Recent phase 1 results with PLX4032/RG7204/vemurafenib, which selectively inhibits B-RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1...


    pub_type: 杂志文章


    authors: Basile KJ,Abel EV,Aplin AE

    更新日期:2012-05-10 00:00:00

  • HUS1 regulates in vivo responses to genotoxic chemotherapies.

    abstract::Cells are under constant attack from genotoxins and rely on a multifaceted DNA damage response (DDR) network to maintain genomic integrity. Central to the DDR are the ATM and ATR kinases, which respond primarily to double-strand DNA breaks (DSBs) and replication stress, respectively. Optimal ATR signaling requires the...


    pub_type: 杂志文章


    authors: Balmus G,Lim PX,Oswald A,Hume KR,Cassano A,Pierre J,Hill A,Huang W,August A,Stokol T,Southard T,Weiss RS

    更新日期:2016-02-04 00:00:00

  • Inhibition of farnesyltransferase increases TGFbeta type II receptor expression and enhances the responsiveness of human cancer cells to TGFbeta.

    abstract::Several small GTPases of the Ras superfamily have been shown to antagonize TGFbeta signaling in human tumor cell lines. Some of these GTPases are post-translationally modified by farnesylation, a lipid modification catalyzed by farnesyltransferase and required for the proteins to attach to membranes and to function. I...


    pub_type: 杂志文章


    authors: Adnane J,Bizouarn FA,Chen Z,Ohkanda J,Hamilton AD,Munoz-Antonia T,Sebti SM

    更新日期:2000-11-16 00:00:00

  • The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines.

    abstract::Promoter hypermethylation is an important means for the transcriptional repression of a number of cancer-associated genes. However, the underlying mechanism of this aberration in cancer remains unclear. Here, we examined 5' CpG island methylation status and expression of the p14(ARF), p16(INK4a) and RASSF1A tumor supp...


    pub_type: 杂志文章


    authors: Sato M,Horio Y,Sekido Y,Minna JD,Shimokata K,Hasegawa Y

    更新日期:2002-07-18 00:00:00

  • Cloning, expression and chromosomal localization of a novel gene for protein tyrosine phosphatase (PTP-U2) induced by various differentiation-inducing agents.

    abstract::Previously, we cloned two gene fragments encoding novel protein tyrosine phosphatases, termed PTP-U1 and PTP-U2. Here, we report the full-length sequence, expression, and chromosomal localization of the PTP-U2 gene. The cDNA for PTP-U2, which was obtained from a human normal kidney library, predicts a protein of 1216 ...


    pub_type: 杂志文章


    authors: Seimiya H,Sawabe T,Inazawa J,Tsuruo T

    更新日期:1995-05-04 00:00:00

  • Notch tumor suppressor function.

    abstract::Cancer development results from deregulated control of stem cell populations and alterations in their surrounding environment. Notch signaling is an important form of direct cell-cell communication involved in cell fate determination, stem cell potential and lineage commitment. The biological function of this pathway ...


    pub_type: 杂志文章,评审


    authors: Dotto GP

    更新日期:2008-09-01 00:00:00

  • Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression.

    abstract::The chromatin organizer SATB1 has been implicated in the development and progression of multiple cancers including breast and colorectal cancers. However, the regulation and role of SATB1 in colorectal cancers is poorly understood. Here, we demonstrate that expression of SATB1 is induced upon hyperactivation of Wnt/β-...


    pub_type: 杂志文章


    authors: Mir R,Pradhan SJ,Patil P,Mulherkar R,Galande S

    更新日期:2016-03-31 00:00:00

  • A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression.

    abstract::Protein arginine methyltransferase 5 (PRMT5) complexed with MEP50/WDR77 catalyzes arginine methylation on histones and other proteins. PRMT5-MEP50 activity is elevated in cancer cells and its expression is highly correlated with poor prognosis in many human tumors. We demonstrate that PRMT5-MEP50 is essential for tran...


    pub_type: 杂志文章


    authors: Chen H,Lorton B,Gupta V,Shechter D

    更新日期:2017-01-19 00:00:00

  • ATM kinase activity modulates ITCH E3-ubiquitin ligase activity.

    abstract::Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3-ubiquitin ligase that modulates the ubiquitination of several targets, therefore part...


    pub_type: 杂志文章


    authors: Santini S,Stagni V,Giambruno R,Fianco G,Di Benedetto A,Mottolese M,Pellegrini M,Barilà D

    更新日期:2014-02-27 00:00:00

  • Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin.

    abstract::It is well known that intracellular antioxidant glutathione (GSH) plays major roles in the maintenance of redox status and defense of oxidative stress. Ras, a small GTP-binding protein, may send growth-stimulating message to the nucleus through downstream Rac oncoprotein and superoxide (O(2*-)). These findings led us ...


    pub_type: 杂志文章


    authors: Chuang JI,Chang TY,Liu HS

    更新日期:2003-03-06 00:00:00

  • Activation of N-ras and K-ras induced by interleukin-6 in a myeloma cell line: implications for disease progression and therapeutic response.

    abstract::Ras is a major signaling molecule activated by interleukin-6. There have been no published reports, however, that specifically examine the kinetics and percentage of Ras activation in response to IL-6. Model cell lines were used to study activation of N- and K-ras induced by IL-6. All of the myeloma cell lines we test...


    pub_type: 杂志文章


    authors: Rowley M,Van Ness B

    更新日期:2002-12-12 00:00:00

  • AP-1 complex is effector of Hox-induced cellular proliferation and transformation.

    abstract::Hox gene products, initially characterized as master regulators of embryonic patterning, are also required for proper functioning of adult tissues. There is also a growing body of evidence that links Hox proteins to regulation of cellular proliferation/transformation. However, the underlying molecular mechanisms of Ho...


    pub_type: 杂志文章


    authors: Krosl J,Sauvageau G

    更新日期:2000-10-26 00:00:00

  • K6 linked polyubiquitylation of FADD by CHIP prevents death inducing signaling complex formation suppressing cell death.

    abstract::Fas-associated death domain (FADD) is an adaptor protein recruiting complexes of caspase 8 to death ligand receptors to induce extrinsic apoptotic cell death in response to a TNF superfamily member. Although, formation of the complex of FADD and caspase 8 upon death stimuli has been studied in detail, posttranslationa...


    pub_type: 杂志文章


    authors: Seo J,Lee EW,Shin J,Seong D,Nam YW,Jeong M,Lee SH,Lee C,Song J

    更新日期:2018-09-01 00:00:00

  • Alternate mechanisms of ras activation are complementary and favor and formation of ras-GTP.

    abstract::The mechanisms of ras activation by mutations in residue 61 and in the NKXD guanine nucleotide-binding consensus sequence (ras residues 116-119) have been evaluated. Weakly transforming mutations that either reduce intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities (61P) or enhance guanine nucl...


    pub_type: 杂志文章


    authors: Patel G,MacDonald MJ,Khosravi-Far R,Hisaka MM,Der CJ

    更新日期:1992-02-01 00:00:00

  • A role for iron in Wnt signalling.

    abstract::There is an emerging body of evidence implicating iron in carcinogenesis and in particular colorectal cancer, but whether this involves Wnt signalling, a major oncogenic signalling pathway has not been studied. We aimed to determine the effect of iron loading on Wnt signalling using mutant APC (Caco-2 and SW480) and w...


    pub_type: 杂志文章


    authors: Brookes MJ,Boult J,Roberts K,Cooper BT,Hotchin NA,Matthews G,Iqbal T,Tselepis C

    更新日期:2008-02-07 00:00:00

  • Roles of the Pas1 and Par2 genes in determination of the unique, intermediate susceptibility of BALB/cByJ mice to urethane-induction of lung carcinogenesis: differential effects on tumor multiplicity, size and Kras2 mutations.

    abstract::The C3H/HeJ (C3H), A/J and BALB/cByJ (BALB) mouse strains are respectively resistant, sensitive and intermediate regarding the induction of lung tumors by urethane. The phenotypic difference between C3H and A/J is largely determined by the Pas1 (Pulmonary adenoma susceptibility 1) gene on chromosome 6, the A/J allele ...


    pub_type: 杂志文章


    authors: Karasaki H,Obata M,Ogawa K,Lee GH

    更新日期:1997-10-09 00:00:00

  • A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis.

    abstract::Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear....


    pub_type: 杂志文章


    authors: Fang WB,Brantley-Sieders DM,Parker MA,Reith AD,Chen J

    更新日期:2005-11-24 00:00:00

  • Development of mammary and cutaneous gland tumors in transgenic mice carrying the RET/PTC1 oncogene.

    abstract::RET/PTC1 is a chimeric oncogene created by the fusion of the tyrosine kinase domain of RET to the 5'-terminal region of another gene named H4. So far, this oncogene has been found activated only in human papillary thyroid carcinomas. In order to investigate its transforming properties in vivo, we have produced transge...


    pub_type: 杂志文章


    authors: Portella G,Salvatore D,Botti G,Cerrato A,Zhang L,Mineo A,Chiappetta G,Santelli G,Pozzi L,Vecchio G,Fusco A,Santoro M

    更新日期:1996-11-07 00:00:00

  • Binding of the corepressor TLE1 to Qin enhances Qin-mediated transformation of chicken embryo fibroblasts.

    abstract::The oncoprotein Qin is a member of the winged helix family of transcriptional regulators. The region C-terminal to its winged helix DNA-binding domain is required for transformation of chicken embryo fibroblasts. We isolated the corepressor TLE1 as a binding partner for Qin in a yeast two-hybrid screen and localized t...


    pub_type: 杂志文章


    authors: Sonderegger CK,Vogt PK

    更新日期:2003-03-27 00:00:00

  • Effects of tumor-suppressor lysyl oxidase propeptide on prostate cancer xenograft growth and its direct interactions with DNA repair pathways.

    abstract::Lysyl oxidase (LOX) is a multifunctional protein required for normal collagen and elastin biosynthesis and maturation. In addition, LOX has complex roles in cancer in which the lysyl oxidase propeptide (LOX-PP) domain of secreted pro-LOX has tumor-suppressor activity, while the active enzyme promotes metastasis. In pr...


    pub_type: 杂志文章


    authors: Bais MV,Ozdener GB,Sonenshein GE,Trackman PC

    更新日期:2015-04-09 00:00:00