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


: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 residue, threonine 286, (Thr-286) which in turn promotes association with the nuclear exportin, CRM1. Mutation of Thr-286 to a non-phosphorylatable residue results in a constitutively nuclear cyclin D1 protein with significantly increased oncogenic potential. To determine whether cyclin D1 is subject to mutations that inhibit its nuclear export in human cancer, we have sequenced exon 5 of cyclin D1 in primary esophageal carcinoma samples and in cell lines derived from esophageal cancer. Our work reveals that cyclin D1 is subject to mutations in primary human cancer. The mutations identified specifically disrupt phosphorylation of cyclin D1 at Thr-286, thereby enforcing nuclear accumulation of cyclin D1. Through characterization of these mutants, we also define an acidic residue within the C-terminus of cyclin D1 that is necessary for recognition and phosphorylation of cyclin D1 by glycogen synthase kinase-3 beta. Finally, through construction of compound mutants, we demonstrate that cell transformation by the cancer-derived cyclin D1 alleles correlates with their ability to associate with and activate CDK4. Our data reveal that cyclin D1 is subject to mutations in primary human cancer that specifically disrupt phosphorylation-dependent nuclear export of cyclin D1 and suggest that such mutations contribute to the genesis and progression of neoplastic growth.






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




Has Abstract


2006-10-12 00:00:00
















  • The induction of uterine leiomyomas and mammary tumors in transgenic mice expressing polyomavirus (PyV) large T (LT) antigen is associated with the ability of PyV LT antigen to form specific complexes with retinoblastoma and CUTL1 family members.

    abstract::The inactivation of certain tumor suppressor genes is thought to play an important role in the genesis of a number of tumor types. For example, inactivation of the Retinoblastoma (Rb) tumor suppressor is frequently observed in a proportion of sporadic human breast cancers. While these studies suggest that inactivation...


    pub_type: 杂志文章


    authors: Webster MA,Martin-Soudant N,Nepveu A,Cardiff RD,Muller WJ

    更新日期:1998-04-16 00:00:00

  • Integrating signals from RTKs to ERK/MAPK.

    abstract::Signals received at the cell surface must be properly transmitted to critical targets within the cell to achieve the appropriate biological response. This process of signal transduction is often initiated by receptor tyrosine kinases (RTKs), which function as entry points for many extracellular cues and play a critica...


    pub_type: 杂志文章,评审


    authors: McKay MM,Morrison DK

    更新日期:2007-05-14 00:00:00

  • Roles of tyrosine residues 845, 892 and 922 in constitutive activation of murine FLT3 kinase domain mutant.

    abstract::FLT3 tyrosine kinase domain (TKD) mutations are detected in approximately 7% of acute myeloid leukemia patients, and suggested to correlate with poor prognosis and confer resistance to FLT3 inhibitors. To explore activation mechanism of FLT3 TKD mutation, we analysed critical tyrosine residues for the constitutive act...


    pub_type: 杂志文章


    authors: Ishiko J,Mizuki M,Matsumura I,Shibayama H,Sugahara H,Scholz G,Serve H,Kanakura Y

    更新日期:2005-12-08 00:00:00

  • Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-kappaB.

    abstract::Transactivating proteins associated with complex onco-retroviruses including human T-cell leukemia virus-1 (HTLV-1) and bovine leukemia virus (BLV) mediate transformation using poorly understood mechanisms. To gain insight into the processes that govern tumor onset and progression, we have examined the impact of BLV-T...


    pub_type: 杂志文章


    authors: Szynal M,Cleuter Y,Beskorwayne T,Bagnis C,Van Lint C,Kerkhofs P,Burny A,Martiat P,Griebel P,Van den Broeke A

    更新日期:2003-07-17 00:00:00

  • The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells.

    abstract::Vascular endothelial growth factor (VEGF) production by stromal fibroblasts plays an important role in tumor angiogenesis. However, VEGF is also expressed by normal tissue fibroblasts, raising the question of how the VEGF activity of fibroblasts is regulated. Here we report that the latent VEGF angiogenic activity of ...


    pub_type: 杂志文章


    authors: Ito TK,Ishii G,Chiba H,Ochiai A

    更新日期:2007-11-08 00:00:00

  • Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model.

    abstract::RAS is a small GTP binding protein mutated in approximately 30% human cancer. Despite its important role in the initiation and progression of human cancer, the underlying mechanism of RAS-induced human epithelial transformation remains elusive. In this study, we probe the cellular and molecular mechanisms of RAS-media...


    pub_type: 杂志文章


    authors: Young T,Mei F,Liu J,Bast RC Jr,Kurosky A,Cheng X

    更新日期:2005-09-08 00:00:00

  • Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma.

    abstract::Microsatellite-stable, near-diploid (MSI-CIN-) colorectal carcinomas have been reported, but it is not clear as to whether these tumours form a discrete group or represent one end of the distribution of MSI-CIN+ cancers. In order to address this question, we screened 23 MSI-CIN- colorectal cancers for gains and losses...


    pub_type: 杂志文章


    authors: Jones AM,Douglas EJ,Halford SE,Fiegler H,Gorman PA,Roylance RR,Carter NP,Tomlinson IP

    更新日期:2005-01-06 00:00:00

  • A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer.

    abstract::Targeted cancer therapies, although often effective, have limited utility owing to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to rep...


    pub_type: 杂志文章


    authors: Kasinski AL,Kelnar K,Stahlhut C,Orellana E,Zhao J,Shimer E,Dysart S,Chen X,Bader AG,Slack FJ

    更新日期:2015-07-01 00:00:00

  • Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA.

    abstract::The Rel/NF-kappaB transcription factors regulate the expression of many genes. The activity of RelA, a member of the Rel/NF-kappaB transcription factor family, is constitutively activated in the majority of pancreatic adenocarcinomas and cell lines. We report that the urokinase-type plasminogen activator (uPA), one of...


    pub_type: 杂志文章


    authors: Wang W,Abbruzzese JL,Evans DB,Chiao PJ

    更新日期:1999-08-12 00:00:00

  • Live imaging of induced and controlled DNA double-strand break formation reveals extremely low repair by homologous recombination in human cells.

    abstract::DNA double-strand breaks (DSBs), the most hazardous DNA lesions, may result in genomic instability, a hallmark of cancer cells. The main DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR). In mammalian cells, NHEJ, which can lead to inaccurate repair, predominates. HR repair (H...


    pub_type: 杂志文章


    authors: Shahar OD,Raghu Ram EV,Shimshoni E,Hareli S,Meshorer E,Goldberg M

    更新日期:2012-07-26 00:00:00

  • Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.

    abstract::Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for poten...


    pub_type: 杂志文章


    authors: Flotho C,Steinemann D,Mullighan CG,Neale G,Mayer K,Kratz CP,Schlegelberger B,Downing JR,Niemeyer CM

    更新日期:2007-08-23 00:00:00

  • Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis.

    abstract::SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING protein required for the activity of Cullin-RING ligase (CRL). Our recent study showed that Sag total knockout caused embryonic lethality at E11.5-12.5 days with associated defects in vasculogenesis. Whether Sag is required for de novo vasculogen...


    pub_type: 杂志文章


    authors: Tan M,Li H,Sun Y

    更新日期:2014-10-30 00:00:00

  • The proto-oncoprotein KR-POK represses transcriptional activation of CDKN1A by MIZ-1 through competitive binding.

    abstract::The BTB/POZ family of proteins has been implicated in multiple biological processes, including tumourigenesis, DNA damage responses and cell cycle progression and development. MIZ-1 (Myc-interacting zinc-finger protein 1) is known to activate transcription of CDKN1A. We recently found that a kidney cancer-related POK ...


    pub_type: 杂志文章


    authors: Lee KM,Choi WI,Koh DI,Kim YJ,Jeon BN,Yoon JH,Lee CE,Kim SH,Oh J,Hur MW

    更新日期:2012-03-15 00:00:00

  • Importin-β/karyopherin-β1 modulates mitotic microtubule function and taxane sensitivity in cancer cells via its nucleoporin-binding region.

    abstract::The nuclear transport receptor importin-β/karyopherin-β1 is overexpressed in cancers that display genomic instability. It is regarded as a promising cancer target and inhibitors are being developed. In addition to its role in nucleo-cytoplasmic transport, importin-β regulates mitosis, but the programmes and pathways i...


    pub_type: 杂志文章


    authors: Verrico A,Rovella P,Di Francesco L,Damizia M,Staid DS,Le Pera L,Schininà ME,Lavia P

    更新日期:2020-01-01 00:00:00

  • K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay.

    abstract::The point mutation that substitutes lysine with arginine at position 120 of human p53 has been characterized as a missense mutation. The K120R mutation renders the p53 protein disabled for acetylation and, as a result, defective for apoptotic function, which provides a mechanistic link between the missense mutation an...


    pub_type: 杂志文章


    authors: Lee SY,Park JH,Jeong S,Kim BY,Kang YK,Xu Y,Chung SK

    更新日期:2019-03-01 00:00:00

  • Transcriptional regulation of A33 antigen expression by gut-enriched Krüppel-like factor.

    abstract::A33 antigen is a membrane-bound protein that is expressed only in intestinal epithelium and in most human colon cancers. Thus, A33 antigen has been explored as a potential therapeutic target for the treatment of colon cancers. However, little is known about the mechanism responsible for the tissue-specific pattern of ...


    pub_type: 杂志文章


    authors: Mao Z,Song S,Zhu Y,Yi X,Zhang H,Shang Y,Tong T

    更新日期:2003-07-10 00:00:00

  • Mutations that abolish the ability of Ha-Ras to associate with Raf-1.

    abstract::Recent studies have revealed that Ras can associate physically with Raf. In the present study, we tested 34 mutants of Ha-Ras carrying substitution(s) in the region of residues 23-71 for their ability to associate with Raf-1. Mouse Ba/F3 cell lysates were incubated with each mutant Ras protein, in either the guanosine...


    pub_type: 杂志文章


    authors: Shirouzu M,Koide H,Fujita-Yoshigaki J,Oshio H,Toyama Y,Yamasaki K,Fuhrman SA,Villafranca E,Kaziro Y,Yokoyama S

    更新日期:1994-08-01 00:00:00

  • GSK3 beta mediates suppression of cyclin D2 expression by tumor suppressor PTEN.

    abstract::PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the tran...


    pub_type: 杂志文章


    authors: Huang W,Chang HY,Fei T,Wu H,Chen YG

    更新日期:2007-04-12 00:00:00

  • Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis.

    abstract::Aurora kinases are known to play a key role in maintaining mitotic fidelity, and overexpression of aurora kinases has been noted in various tumors. Overexpression of aurora kinase activity is thought to promote cancer development through a loss of centrosome or chromosome number integrity. Here we observed augmentatio...


    pub_type: 杂志文章


    authors: Tatsuka M,Sato S,Kitajima S,Suto S,Kawai H,Miyauchi M,Ogawa I,Maeda M,Ota T,Takata T

    更新日期:2005-02-03 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

  • Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains.

    abstract::Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme to identify a rearr...


    pub_type: 杂志文章


    authors: Weinberg F,Griffin R,Fröhlich M,Heining C,Braun S,Spohr C,Iconomou M,Hollek V,Röring M,Horak P,Kreutzfeldt S,Warsow G,Hutter B,Uhrig S,Neumann O,Reuss D,Heiland DH,von Kalle C,Weichert W,Stenzinger A,Brors B,Gli

    更新日期:2020-01-01 00:00:00

  • TGF-beta1 up-regulates paxillin protein expression in malignant astrocytoma cells: requirement for a fibronectin substrate.

    abstract::Cytokines can influence the interactions between members of the integrin cell adhesion receptor family and the extracellular matrix thereby potentially affecting cell function and promoting cell adhesion, growth and migration of malignant astrocytoma tumor cells. As malignant astrocytoma cells synthesize TGF-beta1 in ...


    pub_type: 杂志文章


    authors: Han X,Stewart JE Jr,Bellis SL,Benveniste EN,Ding Q,Tachibana K,Grammer JR,Gladson CL

    更新日期:2001-11-29 00:00:00

  • Induction of epithelial abnormalities that resemble human breast lesions by the expression of the neu/erbB-2 oncogene in reconstituted mouse mammary gland.

    abstract::We have developed a transplantation system that allows us to introduce oncogenes into mouse mammary epithelial cells in culture and then to reconstitute an epithelial tree in vivo from the genetically altered cells. Introduction of the neu oncogene, a transforming homologue of the human proto-oncogene c-erbB-2, produc...


    pub_type: 杂志文章


    authors: Bradbury JM,Arno J,Edwards PA

    更新日期:1993-06-01 00:00:00

  • Identification of genes over-expressed in small cell lung carcinoma using suppression subtractive hybridization and cDNA microarray expression analysis.

    abstract::To identify genes that are differentially over-expressed in Small Cell Lung Carcinoma (SCLC) we have used a combination of suppression subtractive hybridization and cDNA microarray to analyse the expression profiles of 2400 cDNAs clones. Genes that are over-expressed in SCLC were identified using 32 pairs of fluoresce...


    pub_type: 杂志文章


    authors: Bangur CS,Switzer A,Fan L,Marton MJ,Meyer MR,Wang T

    更新日期:2002-05-23 00:00:00

  • Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5.

    abstract::Genomic imprinting at 11p15 is suggested to play a role in certain pediatric tumors such as Wilms' tumor, based on the findings of selective maternal loss of this chromosomal region. Although the allele loss at 11p15 is also frequent in a number of cancers of adults including lung, breast, and bladder cancers, possibl...


    pub_type: 杂志文章


    authors: Kondo M,Matsuoka S,Uchida K,Osada H,Nagatake M,Takagi K,Harper JW,Takahashi T,Elledge SJ,Takahashi T

    更新日期:1996-03-21 00:00:00

  • Complexity of the immediate early response of myeloid cells to terminal differentiation and growth arrest includes ICAM-1, Jun-B and histone variants.

    abstract::Differentiation inducible leukemic as well as normal myeloid precursors treated with physiological myeloid differentiation inducer have been used to explore the immediate early genetic response of cells to terminal differentiation and growth arrest stimuli. cDNA clones of 12 distinct genes, referred to as MyD genes, w...


    pub_type: 杂志文章


    authors: Lord KA,Hoffman-Liebermann B,Liebermann DA

    更新日期:1990-03-01 00:00:00

  • Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma.

    abstract::We have shown earlier that overexpression of Calreticulin (CRT) contributed to a poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). Here, we have shown an important role of CRT in tumorigenesis through enhancing cell motility and anoikis resistance. SiRNA-mediated knockdown of CRT caused impai...


    pub_type: 杂志文章


    authors: Du XL,Yang H,Liu SG,Luo ML,Hao JJ,Zhang Y,Lin DC,Xu X,Cai Y,Zhan QM,Wang MR

    更新日期:2009-10-22 00:00:00

  • Immortalization and transformation of human fibroblasts by regulated expression of polyoma virus T antigens.

    abstract::We have established conditions for the immortalization of human fibroblasts by the large T antigen of the rodent virus polyoma. This allows the mechanism of immortalization to be studied, without interference by transformation events, in cells with relatively stable chromosomes. Large T antigen could immortalize human...


    pub_type: 杂志文章


    authors: Strauss M,Hering S,Lubbe L,Griffin BE

    更新日期:1990-08-01 00:00:00

  • Epstein-Barr virus latent membrane protein-1 (LMP1) signalling is distinct from CD40 and involves physical cooperation of its two C-terminus functional regions.

    abstract::The Epstein-Barr virus (EBV) encoded Latent Membrane Protein-1 (LMP1) mimics a constitutively active receptor molecule, and has been shown to activate NF-kappaB and the MAPK and JNK pathways. Two regions within the cytosolic domain of LMP1 have been found to effect cell signalling. One of these, the carboxy-terminal a...


    pub_type: 杂志文章


    authors: Floettmann JE,Eliopoulos AG,Jones M,Young LS,Rowe M

    更新日期:1998-11-05 00:00:00

  • NF-kappaB/RelA transactivation is required for atypical protein kinase C iota-mediated cell survival.

    abstract::In chronic myelogenous leukemia (CML), the oncogene bcr-abl encodes a dysregulated tyrosine kinase that inhibits apoptosis. We showed previously that human erythroleukemia K562 cells are resistant to antineoplastic drug (taxol)-induced apoptosis through the atypical protein kinase C iota isozyme (PKC iota), a kinase d...


    pub_type: 杂志文章


    authors: Lu Y,Jamieson L,Brasier AR,Fields AP

    更新日期:2001-08-09 00:00:00