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
















  • Delayed cyclin B1 expression during the G2 arrest following DNA damage.

    abstract::Exposure of cells to DNA damaging agents results in a G2 arrest. Exposure of HeLa cells to camptothecin, etoposide or nitrogen mustard for 1 h in S phase resulted in delayed expression of cyclin B1 mRNA during the G2 arrest. Initially the levels of cyclin B1 protein were low as well; however, with extended time the ce...


    pub_type: 杂志文章


    authors: Maity A,Hwang A,Janss A,Phillips P,McKenna WG,Muschel RJ

    更新日期:1996-10-17 00:00:00

  • Induction of p53, p21 and apoptosis by silencing the NF90/NF45 complex in human papilloma virus-transformed cervical carcinoma cells.

    abstract::The heterodimeric nuclear factor (NF) 90/NF45 complex (NF90/NF45) binds nucleic acids and is a multifunctional regulator of gene expression. Here we report that depletion of NF90/NF45 restores the expression of the p53 and p21 proteins in cervical carcinoma cells infected with high-risk human papillomaviruses (HPVs). ...


    pub_type: 杂志文章


    authors: Shamanna RA,Hoque M,Pe'ery T,Mathews MB

    更新日期:2013-10-24 00:00:00

  • Repression of hepatitis B virus (HBV) transgene and HBV-induced liver injury by low protein diet.

    abstract::Persistent infection with hepatitis B virus (HBV) is one of the primary risk factors for human hepatocellular carcinoma (HCC). In a human ecological study, we have shown that, in addition to HBV, animal food consumption also significantly contributes to the variance of HCC. To test the interacting effect of HBV and an...


    pub_type: 杂志文章


    authors: Hu JF,Cheng Z,Chisari FV,Vu TH,Hoffman AR,Campbell TC

    更新日期:1997-12-04 00:00:00

  • Chimaerism and erythroid marker expression after microinjection of human acute myeloid leukaemia cells into murine blastocysts.

    abstract::It has been suggested that the embryonic microenvironment can control the survival and the transformed phenotype of tumour cells. Here, we addressed the hypothesis that the murine embryonic microenvironment can induce the differentiation of human tumour cells. To examine such interactions, we injected human leukaemic ...


    pub_type: 杂志文章


    authors: Dürr M,Harder F,Merkel A,Bug G,Henschler R,Müller AM

    更新日期:2003-12-11 00:00:00

  • A new candidate site for a tumor suppressor gene involved in mouse thymic lymphomagenesis is located on the distal part of chromosome 4.

    abstract::In a previous work we provided preliminary evidence of the existence of a putative tumor suppressor gene region on the distal part of chromosome 4 in gamma-radiation-induced T-cell lymphomas of (C57BL/6J x RF/J) F1 hybrid mice. This region, named as TLSR2 (Thymic Lymphoma Suppressor Region 2), was located centered at ...


    pub_type: 杂志文章


    authors: Santos J,Herranz M,Pérez de Castro I,Pellicer A,Fernández-Piqueras J

    更新日期:1998-08-20 00:00:00

  • Allelic loss at 7q31.1 in human primary ovarian carcinomas suggests the existence of a tumor suppressor gene.

    abstract::We studied loss of heterozygosity (LOH) in chromosome 7q in order to determine the location of a putative tumor suppressor gene (TSG) in human epithelial ovarian carcinomas. Samples were obtained from 26 primary ovarian carcinomas at the time of staging laparotomy. Paired normal and tumoral DNAs were used as templates...


    pub_type: 杂志文章


    authors: Zenklusen JC,Weitzel JN,Ball HG,Conti CJ

    更新日期:1995-07-20 00:00:00

  • CHK2-mediated regulation of PARP1 in oxidative DNA damage response.

    abstract::Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor, which upon activation, recruits downstream proteins by poly(ADP-ribosyl)ation (PARylation). However, it remains largely unclear how PARP1 activity is regulated. Interestingly, the data obtained through this study revealed that PARP1 was co-immunoprecipitate...


    pub_type: 杂志文章


    authors: Hsu PC,Gopinath RK,Hsueh YA,Shieh SY

    更新日期:2019-02-01 00:00:00

  • CHTM1, a novel metabolic marker deregulated in human malignancies.

    abstract::A better understanding of the link between cellular metabolism and tumorigenesis is needed. Here, we report characterization of a novel protein named coiled-coil helix tumor and metabolism 1 (CHTM1). We have found that CHTM1 is associated with cancer and cellular metabolism. CHTM1 localizes to mitochondria and cytosol...


    pub_type: 杂志文章


    authors: Babbar M,Huang Y,An J,Landas SK,Sheikh MS

    更新日期:2018-04-01 00:00:00

  • The PGC-1/ERR signaling axis in cancer.

    abstract::Proliferating cells need to produce a large amount of energy and, at the same time, need to maintain a constant supply of biosynthetic precursors of macromolecules that are used as building blocks for generating new cells. Indeed, many cancer cells undergo a switch from mitochondrial to glycolytic metabolism and displ...


    pub_type: 杂志文章,评审


    authors: Deblois G,St-Pierre J,Giguère V

    更新日期:2013-07-25 00:00:00

  • Ras controls coupling of growth factor receptors and protein kinase C in the membrane to Raf-1 and B-Raf protein serine kinases in the cytosol.

    abstract::A dominant negative mutant of Ras, M17 Ras, was used to study the role of Ras in receptor coupling of Raf-1 and B-Raf protein serine/threonine kinases (PSKs). We found that mutant Ras blocks serum- and 12-O-tetradecanoyl phorbol 13-acetate-induced activation of Raf-1 kinase in NIH3T3 cells and Raf-1 as well as B-Raf P...


    pub_type: 杂志文章


    authors: Troppmair J,Bruder JT,App H,Cai H,Liptak L,Szeberényi J,Cooper GM,Rapp UR

    更新日期:1992-09-01 00:00:00

  • The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair.

    abstract::Loss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late-onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3(-...


    pub_type: 杂志文章


    authors: van Oers JM,Edwards Y,Chahwan R,Zhang W,Smith C,Pechuan X,Schaetzlein S,Jin B,Wang Y,Bergman A,Scharff MD,Edelmann W

    更新日期:2014-07-24 00:00:00

  • Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis.

    abstract::Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein that is part of the carcinoembryonic antigen and the immunoglobulin superfamilies. We have shown that it functions as a tumor suppressor and that this function depends upon the presence of the longer CEACAM1 cytoplasmic domain. In th...


    pub_type: 杂志文章


    authors: Leung N,Turbide C,Olson M,Marcus V,Jothy S,Beauchemin N

    更新日期:2006-09-07 00:00:00

  • The HIF and other quandaries in VHL disease.

    abstract::Mutations in VHL underlie von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome with several subtypes depending on the risk of developing certain combination of classic features, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma and pheochromocytoma. Although numerous potential substrates and f...


    pub_type: 杂志文章,评审


    authors: Tarade D,Ohh M

    更新日期:2018-01-11 00:00:00

  • Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt.

    abstract::Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid...


    pub_type: 杂志文章


    authors: Han YH,Cao X,Lin B,Lin F,Kolluri SK,Stebbins J,Reed JC,Dawson MI,Zhang XK

    更新日期:2006-05-18 00:00:00

  • Mysterious liaisons: the relationship between c-Myc and the cell cycle.

    abstract::A large body of physiological evidence shows that either upregulation or downregulation of intracellular c-Myc activity has profound consequences on cell cycle progression. Recent work suggests that c-Myc may stimulate the activity of cyclin E/cyclin-dependent kinase 2 (Cdk2) complexes and antagonize the action of the...


    pub_type: 杂志文章,评审


    authors: Obaya AJ,Mateyak MK,Sedivy JM

    更新日期:1999-05-13 00:00:00

  • Regulation of cell migration, invasion and metastasis by IAP proteins and their antagonists.

    abstract::Inhibitor of apoptosis (IAP) proteins are a family comprised of a total of eight mammalian members that were initially described to act as endogenous inhibitors of caspases. In addition, extensive evidence has been accumulated over the last years showing that IAP proteins can regulate various signal transduction pathw...


    pub_type: 杂志文章,评审


    authors: Fulda S

    更新日期:2014-02-06 00:00:00

  • Identification and analysis of the ret proto-oncogene promoter region in neuroblastoma cell lines and medullary thyroid carcinomas from MEN2A patients.

    abstract::The human ret proto-oncogene (proto-ret), encoding a receptor tyrosine kinase, is highly expressed in neuroblastomas, medullary thyroid carcinomas (MTCs) and pheochromocytomas, which are all tumors of cells originating from the neural crest. In studies on the transcription mechanism of proto-ret, we identified the tra...


    pub_type: 杂志文章


    authors: Itoh F,Ishizaka Y,Tahira T,Yamamoto M,Miya A,Imai K,Yachi A,Takai S,Sugimura T,Nagao M

    更新日期:1992-06-01 00:00:00

  • A novel mitochondrial amidoxime reducing component 2 is a favorable indicator of cancer and suppresses the progression of hepatocellular carcinoma by regulating the expression of p27.

    abstract::Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime...


    pub_type: 杂志文章


    authors: Wu D,Wang Y,Yang G,Zhang S,Liu Y,Zhou S,Guo H,Liang S,Cui Y,Zhang B,Ma K,Zhang C,Liu Y,Sun L,Wang J,Liu L

    更新日期:2020-09-01 00:00:00

  • Expression of beta-galactosidase under the control of the human c-myc promoter in transgenic mice is inhibited by mithramycin.

    abstract::In order to assess the functional contribution of the human c-myc promoter region in the expression of the c-myc gene, transgenic mouse lines containing a bacterial lac Z gene encoding beta-galactosidase under the control of the human c-myc protooncogene promoter were generated. Transgenic mouse embryos heterozygous f...


    pub_type: 杂志文章


    authors: Jones DE Jr,Cui DM,Miller DM

    更新日期:1995-06-15 00:00:00

  • Isolation of human fos-related genes and their expression during monocyte-macrophage differentiation.

    abstract::cDNA clones of human fos-related genes fra-1 and fra-2 were isolated by screening human c-DNA libraries with human fos DNA as a probe. We obtained human fra-1 cDNA clones that can code for a protein of 271 amino acid residues with a calculated molecular weight of 29,413 and showed 90% similarity with rat fra-1 protein...


    pub_type: 杂志文章


    authors: Matsui M,Tokuhara M,Konuma Y,Nomura N,Ishizaki R

    更新日期:1990-03-01 00:00:00

  • Apoptosis and melanoma chemoresistance.

    abstract::Melanoma is the most aggressive form of skin cancer and is notoriously resistant to all current modalities of cancer therapy. A large set of genetic, functional and biochemical studies suggest that melanoma cells become 'bullet proof' against a variety of chemotherapeutic drugs by exploiting their intrinsic resistance...


    pub_type: 杂志文章,评审


    authors: Soengas MS,Lowe SW

    更新日期:2003-05-19 00:00:00

  • Loss of IGFBP7 expression and persistent AKT activation contribute to SMARCB1/Snf5-mediated tumorigenesis.

    abstract::SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. SMARCB1 is a core subunit of Swi/Snf chromatin remodeling complexes, and loss ...


    pub_type: 杂志文章


    authors: Darr J,Klochendler A,Isaac S,Eden A

    更新日期:2014-06-05 00:00:00

  • TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.

    abstract::TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). T...


    pub_type: 杂志文章


    authors: Ochiiwa H,Ailiken G,Yokoyama M,Yamagata K,Nagano H,Yoshimura C,Muraoka H,Ishida K,Haruma T,Nakayama A,Hashimoto N,Murata K,Nishimura M,Kawashima Y,Ohara O,Ohkubo S,Tanaka T

    更新日期:2021-01-08 00:00:00

  • Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31.

    abstract::The most common genetic alteration identified in transitional cell carcinoma (TCC) of the bladder is loss of heterozygosity (LOH) on chromosome 9. However, localization of tumor suppressor genes on 9q has been hampered by the low frequency of subchromosomal deletions. We have analysed 139 primary, initial low stage TC...


    pub_type: 杂志文章


    authors: Simoneau M,Aboulkassim TO,LaRue H,Rousseau F,Fradet Y

    更新日期:1999-01-07 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

  • Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice.

    abstract::The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix-loop-helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in c...


    pub_type: 杂志文章


    authors: Rankin EB,Rha J,Unger TL,Wu CH,Shutt HP,Johnson RS,Simon MC,Keith B,Haase VH

    更新日期:2008-09-11 00:00:00

  • Restriction and complexity of Mcf2 proto-oncogene expression.

    abstract::MCF2/DBL is an X-linked proto-oncogene encoding a protein with a yet undetermined function. It can be activated in vitro by loss of 5' sequences in NIH3T3 bioassays; in vivo, deletion of the gene has been found in some hemophilia B patients. PCR analysis of its expression in mouse tissues shows a restriction to the go...


    pub_type: 杂志文章


    authors: Galland F,Pirisi V,de Lapeyriere O,Birnbaum D

    更新日期:1991-05-01 00:00:00

  • The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family.

    abstract::Apoptosis is essential for normal development and maintenance of homeostasis, and disruption of apoptotic pathways is associated with multiple disease states, including cancer. Although initially identified as central regulators of apoptosis at the level of mitochondria, an important role for BCL-2 proteins at the end...


    pub_type: 杂志文章,评审


    authors: Heath-Engel HM,Chang NC,Shore GC

    更新日期:2008-10-27 00:00:00

  • Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells.

    abstract::Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-...


    pub_type: 杂志文章


    authors: Ehrhardt H,Häcker S,Wittmann S,Maurer M,Borkhardt A,Toloczko A,Debatin KM,Fulda S,Jeremias I

    更新日期:2008-01-31 00:00:00

  • p66(Shc) and Ras: controlling anoikis from the inside-out.

    abstract::Protection from detachment-induced cell death, termed anoikis, facilitates metastasis. Though anoikis is largely attributed to the loss of integrin-related 'outside-in' survival signals, Terada and colleagues demonstrate a novel 'inside-out' attachment sensing role for the adapter protein p66(Shc) in promoting anoikis...


    pub_type: 评论,杂志文章


    authors: Debnath J

    更新日期:2010-10-14 00:00:00