Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients.


:Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 microM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.






Tamborini E,Pricl S,Negri T,Lagonigro MS,Miselli F,Greco A,Gronchi A,Casali PG,Ferrone M,Fermeglia M,Carbone A,Pierotti MA,Pilotti S




Has Abstract


2006-10-05 00:00:00
















  • Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer.

    abstract::Prostate stem cell antigen (PSCA) is a recently defined homologue of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA mRNA is expressed in the basal cells of normal prostate and in more than 80% of prostate cancers. The purpose of the present study was to examine PSCA pr...


    pub_type: 杂志文章


    authors: Gu Z,Thomas G,Yamashiro J,Shintaku IP,Dorey F,Raitano A,Witte ON,Said JW,Loda M,Reiter RE

    更新日期:2000-03-02 00:00:00

  • Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4.

    abstract::Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. Here, we...


    pub_type: 杂志文章


    authors: Harjes U,Bridges E,Gharpure KM,Roxanis I,Sheldon H,Miranda F,Mangala LS,Pradeep S,Lopez-Berestein G,Ahmed A,Fielding B,Sood AK,Harris AL

    更新日期:2017-02-16 00:00:00

  • Wnts as ligands: processing, secretion and reception.

    abstract::Cell to cell communication is vital throughout the development of multicellular organisms and during adult homeostasis. One way in which communication is achieved is through the secretion of signaling molecules that are received by neighboring responding cells. Wnt ligands comprise a large family of secreted, hydropho...


    pub_type: 杂志文章,评审


    authors: Mikels AJ,Nusse R

    更新日期:2006-12-04 00:00:00

  • SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol.

    abstract::The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study th...


    pub_type: 杂志文章


    authors: Boily G,He XH,Pearce B,Jardine K,McBurney MW

    更新日期:2009-08-13 00:00:00

  • Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.

    abstract::Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired ...


    pub_type: 杂志文章


    authors: Shiu KK,Wetterskog D,Mackay A,Natrajan R,Lambros M,Sims D,Bajrami I,Brough R,Frankum J,Sharpe R,Marchio C,Horlings H,Reyal F,van der Vijver M,Turner N,Reis-Filho JS,Lord CJ,Ashworth A

    更新日期:2014-01-30 00:00:00

  • Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis.

    abstract::To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGFbeta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFbeta exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFbeta for 2-5 days, w...


    pub_type: 杂志文章


    authors: Gal A,Sjöblom T,Fedorova L,Imreh S,Beug H,Moustakas A

    更新日期:2008-02-21 00:00:00

  • BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines.

    abstract::BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negat...


    pub_type: 杂志文章


    authors: Herr R,Halbach S,Heizmann M,Busch H,Boerries M,Brummer T

    更新日期:2018-03-01 00:00:00

  • The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia.

    abstract::Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional chemotherapy treatment approaches. CLL as a disease entity is defined by a relatively parsimonious set of diagnostic criteria and therefore likely constitutes an umbrella term for multiple relate...


    pub_type: 杂志文章,评审


    authors: Malek SN

    更新日期:2013-06-06 00:00:00

  • IL-6-independent expression of Mcl-1 in human multiple myeloma.

    abstract::Mcl-1 is a critical antiapoptotic survival factor for human multiple myeloma (MM). We examined the importance of IL-6 for Mcl-1 expression in five MM cell lines and in primary MM cells from 14 patients. While culture of MM.1S cells in IL-6 did induce Mcl-1 expression, four other MM cell lines exhibited high levels of ...


    pub_type: 杂志文章


    authors: Zhang B,Potyagaylo V,Fenton RG

    更新日期:2003-03-27 00:00:00

  • Tamoxifen overrides autophagy inhibition in Beclin-1-deficient glioma cells and their resistance to adenovirus-mediated oncolysis via upregulation of PUMA and BAX.

    abstract::Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism...


    pub_type: 杂志文章


    authors: Kaverina NV,Kadagidze ZG,Borovjagin AV,Karseladze AI,Kim CK,Lesniak MS,Miska J,Zhang P,Baryshnikova MA,Xiao T,Ornelles D,Cobbs C,Khramtsov A,Ulasov IV

    更新日期:2018-11-01 00:00:00

  • MUC1-C activates BMI1 in human cancer cells.

    abstract::B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overex...


    pub_type: 杂志文章


    authors: Hiraki M,Maeda T,Bouillez A,Alam M,Tagde A,Hinohara K,Suzuki Y,Markert T,Miyo M,Komura K,Ahmad R,Rajabi H,Kufe D

    更新日期:2017-05-18 00:00:00

  • Polymorphisms in the p53 pathway.

    abstract::The p53 tumor suppressor gene continues to be distinguished as the most frequently mutated gene in human cancer; this gene can be found mutated in up to 50% of human tumors of diverse histological type. It is generally accepted that the ability of p53 to induce either growth arrest or programmed cell death in response...


    pub_type: 杂志文章,评审


    authors: Pietsch EC,Humbey O,Murphy ME

    更新日期:2006-03-13 00:00:00

  • New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin.

    abstract::Telomeres are stabilized, and telomeric DNA is replenished, by the action of the ribonucleoprotein reverse transcriptase telomerase. Telomere capping functions include the ability of telomeres to protect chromosome ends from cellular DNA-damage responses such as cell cycle arrest or apoptosis. This property of telomer...


    pub_type: 杂志文章,评审


    authors: Chan SW,Blackburn EH

    更新日期:2002-01-21 00:00:00

  • The tyrosine kinase Abl is required for Src-transforming activity in mouse fibroblasts and human breast cancer cells.

    abstract::The cytoplasmic tyrosine kinase Src has been implicated in signal transduction induced by growth factors and integrins. Src also shows oncogenic activity when deregulated. Accumulating evidence indicates that the tyrosine kinase Abl is an important substrate for Src signalling in normal cells. Here we show that Abl is...


    pub_type: 杂志文章


    authors: Sirvent A,Boureux A,Simon V,Leroy C,Roche S

    更新日期:2007-11-15 00:00:00

  • Down-regulation of NF-kappaB activity and NF-kappaB p65 subunit expression by ras and polyoma middle T oncogenes in human colonic Caco-2 cells.

    abstract::The products of ras and src proto-oncogenes are frequently activated in a constitutive state in human colorectal cancer. In this study we attempted to establish whether the tumorigenic progression induced by oncogenic activation of p21ras or pp60c-src in human colonic cells is associated with alterations of the activi...


    pub_type: 杂志文章


    authors: Cadoret A,Bertrand F,Baron-Delage S,Lévy P,Courtois G,Gespach C,Capeau J,Cherqui G

    更新日期:1997-04-03 00:00:00

  • Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer.

    abstract::Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LN...


    pub_type: 杂志文章


    authors: Urbanucci A,Sahu B,Seppälä J,Larjo A,Latonen LM,Waltering KK,Tammela TL,Vessella RL,Lähdesmäki H,Jänne OA,Visakorpi T

    更新日期:2012-04-26 00:00:00

  • Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1.

    abstract::Although cyclin D1 is overexpressed in a significant number of human cancers, overexpression alone is insufficient to promote tumorigenesis. In vitro studies have revealed that inhibition of cyclin D1 nuclear export unmasks its neoplastic potential. Cyclin D1 nuclear export depends upon phosphorylation of a C-terminal...


    pub_type: 杂志文章


    authors: Benzeno S,Lu F,Guo M,Barbash O,Zhang F,Herman JG,Klein PS,Rustgi A,Diehl JA

    更新日期:2006-10-12 00:00:00

  • Differential modulation of Myb family genes by Ets-2.

    abstract::The myb family of genes encodes highly homologous nuclear transcription factors that play distinct roles in the development of breast, germ cells and hematoid organs. While the mechanisms associated with the regulation of these genes remain unknown, the transactivation of c-Myb was previously shown to be upregulated b...


    pub_type: 杂志文章


    authors: Kang AD,Park G,Kim YH,Oh IH

    更新日期:2004-05-20 00:00:00

  • Mouse models in the study of the Ets family of transcription factors.

    abstract::The Ets family of transcription factors is one of a growing number of master regulators of development. This family was originally defined by the presence of a conserved DNA binding domain, the Ets domain. To date, nearly 30 members of this family have been identified and implicated in a wide range of physiological an...


    pub_type: 杂志文章,评审


    authors: Bartel FO,Higuchi T,Spyropoulos DD

    更新日期:2000-12-18 00:00:00

  • Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage.

    abstract::The p53-regulated GADD45 gene is one of the important players in cellular response to DNA damage, and probably involved in the control of cell cycle checkpoint, apoptosis and DNA repair. There are both the p53-dependent and -independent pathways that regulate GADD45 induction. Following ionizing radiation, induction o...


    pub_type: 杂志文章


    authors: Jin S,Fan F,Fan W,Zhao H,Tong T,Blanck P,Alomo I,Rajasekaran B,Zhan Q

    更新日期:2001-05-10 00:00:00

  • The amplicons in HL60 cells contain novel cellular sequences linked to MYC locus DNA.

    abstract::We have previously determined that the amplified DNA present in the HL60 promyelocytic leukaemia cell line contained 70 kb of continuous DNA sequences around the c-myc gene. In the work presented here we have further defined the HL60 amplicon and find it to be of the order of 160 kb and to contain a large region of DN...


    pub_type: 杂志文章


    authors: Feo S,Di Liegro C,Mangano R,Read M,Fried M

    更新日期:1996-10-03 00:00:00

  • Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer.

    abstract::Tumor metastasis is the leading cause of death among breast cancer patients. PELP1 (proline, glutamic acid and leucine rich protein 1) is a nuclear receptor coregulator that is upregulated during breast cancer progression to metastasis and is an independent prognostic predictor of shorter survival of breast cancer pat...


    pub_type: 杂志文章


    authors: Roy SS,Gonugunta VK,Bandyopadhyay A,Rao MK,Goodall GJ,Sun LZ,Tekmal RR,Vadlamudi RK

    更新日期:2014-07-10 00:00:00

  • Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model.

    abstract::Acute myeloid leukemia (AML) is a heterogeneous disease comprising a large number of subtypes defined by specific chromosome abnormalities. One such subtype carries the t(6;9)(p22;q34) chromosome rearrangement, which leads to expression of the DEK-NUP214 chimeric gene, and has a particularly poor outcome. To provide a...


    pub_type: 杂志文章


    authors: Qin H,Malek S,Cowell JK,Ren M

    更新日期:2016-10-27 00:00:00

  • Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma.

    abstract::Heterozygous germline mutations in PHOX2B, a transcriptional regulator of sympathetic neuronal differentiation, predispose to diseases of the sympathetic nervous system, including neuroblastoma and congenital central hypoventilation syndrome (CCHS). Although the PHOX2B variants in CCHS largely involve expansions of th...


    pub_type: 杂志文章


    authors: Wang W,Zhong Q,Teng L,Bhatnagar N,Sharma B,Zhang X,Luther W 2nd,Haynes LP,Burgoyne RD,Vidal M,Volchenboum S,Hill DE,George RE

    更新日期:2014-06-19 00:00:00

  • Stat5 activation inhibits prolactin-induced AP-1 activity: distinct prolactin-initiated signals in tumorigenesis dependent on cell context.

    abstract::The essential role of prolactin (PRL) in normal mammary gland growth and differentiation has implicated this hormone in the development and progression of breast cancer. Although Stat5 is the best-characterized mediator of PRL signals, PRL also activates multiple other signals, whose roles in normal and pathologic pro...


    pub_type: 杂志文章


    authors: Gutzman JH,Rugowski DE,Nikolai SE,Schuler LA

    更新日期:2007-09-20 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

  • Expression of the naturally occurring truncated trkB neurotrophin receptor induces outgrowth of filopodia and processes in neuroblastoma cells.

    abstract::We have investigated the effects of the truncated trkB receptor isoform T1 (trkB.T1) by transient transfection into mouse N2a neuroblastoma cells. We observed that expression of trkB.T1 leads to a striking change in cell morphology characterized by outgrowth of filopodia and processes. A similar morphological response...


    pub_type: 杂志文章


    authors: Haapasalo A,Saarelainen T,Moshnyakov M,Arumäe U,Kiema TR,Saarma M,Wong G,Castrén E

    更新日期:1999-02-11 00:00:00

  • Isolation of a new class of 'flat' revertants from ras-transformed NIH3T3 cells using cis-4-hydroxy-L-proline.

    abstract::A new class of nontransformed revertant cells has been isolated from the ras-transformed cell line DT using cis-4-hydroxy-L-proline (CHP) as a selective agent. The new revertants, CHP 9CJ and CHP CB4, each contain two copies of the v-Ki-ras gene, elevated levels of phosphorylated p21ras protein, and rescuable transfor...


    pub_type: 杂志文章


    authors: Yanagihara K,Ciardiello F,Talbot N,McGeady ML,Cooper H,Benade L,Salomon DS,Bassin RH

    更新日期:1990-08-01 00:00:00

  • Metabotropic glutamate receptor subtype-1 is essential for in vivo growth of melanoma.

    abstract::Ectopic expression of metabotropic glutamate receptor subtype 1 (mGluR1) in mouse melanocytes induces melanoma formation. Although requirement of mGluR1 for development of melanoma in the initial stage has been demonstrated, its role in melanoma growth in vivo remains unclear. In this study, we developed novel transge...


    pub_type: 杂志文章


    authors: Ohtani Y,Harada T,Funasaka Y,Nakao K,Takahara C,Abdel-Daim M,Sakai N,Saito N,Nishigori C,Aiba A

    更新日期:2008-12-04 00:00:00

  • Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin.

    abstract::Previously, we have mimicked human neurofibromatosis type 2 (NF2) in conditional Nf2 mutant (P0Cre;Nf2flox2/flox2) mice. Schwannomas, characteristic for NF2, were found at low frequency in older mice. Here, we report that these mice, upon additional hemizygosity for p53, rapidly develop multiple tumours showing featur...


    pub_type: 杂志文章


    authors: Robanus-Maandag E,Giovannini M,van der Valk M,Niwa-Kawakita M,Abramowski V,Antonescu C,Thomas G,Berns A

    更新日期:2004-08-26 00:00:00