Cancer-associated mis-sense and deletion mutations impair p16INK4 CDK inhibitory activity.


:The p16INK4 gene is a candidate tumour-suppressor gene which maps to the genomic locus 9p21, and mutations of this gene are associated with melanoma and other cancers. Biochemical studies suggest that p16INK4 mediates its effects by specifically inhibiting the G1 cyclin-dependent kinases CDK4 and CDK6, thereby regulating the progression through G1 into S phase of the cell cycle. To evaluate the functional effects of mutations in p16INK4 which have been observed in primary cancers and cancer cell lines, we constructed a series of deletion mutants comprising amino acid regions 9-72, 9-131, 73-131 and 73-156; a mis-sense mutation identified in melanoma (Arg87Pro); and the polymorphism Ala48Thr and investigated their ability to inhibit cyclin D1/CDK4 kinase activity in vitro. Removal of 25 amino acids from the carboxy terminus of p16INIK4 (9-131) had little impact on its inhibitory activity. In contrast, deletion of the 65 N-terminal amino acids comprising the first and second ankyrin repeats of p16INK4 (73-131) abolished its inhibitory activity. The carboxy (73-156) and amino termial (9-72) fragments of p16INK4 also failed to inhibit cyclin D1/CDK4 activity. These results indicate that the core region (73-131) as well as amino acids N-terminal of this sequence are important, whereas sequences C-terminal of amino acid 131 are less important for the inhibitory activity of this molecule. The melanoma-associated Arg87Pro mutation resulted in loss of inhibitory activity, whereas the Ala148Thr polymorphic variant was as effective as the alanine variant of p16INK4 in inhibiting D1/CDK4 kinase activity. Binding assays revealed that inhibition was invariably associated with p16INK4 binding to CDK4. Hence, our studies indicate that minor perturbations in p16INK4 primary structure can lead to loss of its inhibitory activity, possibly contributing to oncogenesis in numerous cell types.


Int J Cancer


Lilischkis R,Sarcevic B,Kennedy C,Warlters A,Sutherland RL




Has Abstract


1996-04-10 00:00:00














  • Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines.

    abstract::Wnt signaling pathway activation via mutation of genetic components, commonly adenomatous polyposis coli (APC), has a major role in colorectal cancer (CRC). Most components have not been assessed for mutation in sporadic CRC. We have analyzed AXIN2, CK1alpha, DKK1, GSK-3beta, SOX17, LRP6 and PPP2R1B, beta-catenin and ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Suraweera N,Robinson J,Volikos E,Guenther T,Talbot I,Tomlinson I,Silver A

    更新日期:2006-10-15 00:00:00

  • A BALB/c 3T3-transformed cell line suitable for transfection assay of metastasis-inducing genes.

    abstract::A clonal cell line, 1-1ras1000, transformed by the activated c-Ha-ras oncogene, does not form metastases after i.v. injection into mice (experimental metastasis assay). Here, we show that this cell line is useful as a recipient to detect metastasis-inducing genes, using a transfection assay. Cells (1-1ras1000) were su...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Tatsuka M,Ota T,Maeda M,Wada M,Yamagishi N,Taniguchi S,Seiki M,Odashima S

    更新日期:1997-03-28 00:00:00

  • Exposure to environmental tobacco smoke and risk of adenocarcinoma of the lung.

    abstract::We conducted a case-control study of adenocarcinoma of the lung and exposure to environmental tobacco smoke (ETS) in 7 countries. We interviewed 70 cases of adenocarcinoma of the lung and 178 population or hospital controls. All subjects had smoked fewer than 400 cigarettes in their lifetimes. Ever exposure to ETS fro...

    journal_title:International journal of cancer

    pub_type: 杂志文章,多中心研究


    authors: Boffetta P,Ahrens W,Nyberg F,Mukeria A,Brüske-Hohlfeld I,Fortes C,Constantinescu V,Simonato L,Batura-Gabryel H,Lea S,Gaborieau V,Benhamou S

    更新日期:1999-11-26 00:00:00

  • Effects of NQO1 deficiency on levels of cyclopurines and other oxidative DNA lesions in liver and kidney of young mice.

    abstract::I-compounds are bulky indigenous DNA adducts that can be detected by (32)P-postlabeling. A subgroup, termed type II I-compounds, represents DNA lesions induced by oxidative stress. Several major type II I-compounds have been identified as dinucleotides containing 3'-terminal 8,5'-cyclo-2'-deoxyadenosine (cA). Levels o...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Zhou GD,Randerath K,Donnelly KC,Jaiswal AK

    更新日期:2004-12-10 00:00:00

  • Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines.

    abstract::The tumor-suppressor genes p14(ARF), p16(INK4a) and Tp53 are commonly inactivated in many tumors. We investigated their role in the pathogenesis of 9 bile tract cancer cell lines and 21 primary sporadic extrahepatic bile duct carcinomas. p53 and p16 protein expression was examined by Western blot analysis and immunohi...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Caca K,Feisthammel J,Klee K,Tannapfel A,Witzigmann H,Wittekind C,Mössner J,Berr F

    更新日期:2002-02-01 00:00:00

  • Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells.

    abstract::Our study explored the drug interaction of all-trans retinoic acid (ATRA) and RAD001 (everolimus), the inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in acute myelogenous leukemia (AML) NB4 and HL60 cells. RAD001 (10 nM) significantly enhanced the ATRA-induced growth arrest and differentiation of these...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Nishioka C,Ikezoe T,Yang J,Gery S,Koeffler HP,Yokoyama A

    更新日期:2009-10-01 00:00:00

  • RNAi-mediated downregulation of urokinase plasminogen activator receptor and matrix metalloprotease-9 in human breast cancer cells results in decreased tumor invasion, angiogenesis and growth.

    abstract::The serine protease urokinase-type plasminogen activator (uPA) plays a significant role in tumor cell invasion and metastasis when bound to its specific receptor, uPAR (also known as CD87). In addition to the uPA-uPAR system, matrix metalloproteinases (MMPs) are involved in tumor cell invasion and metastasis. In this ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Kunigal S,Lakka SS,Gondi CS,Estes N,Rao JS

    更新日期:2007-11-15 00:00:00

  • Postdiagnosis weight change is associated with poorer survival in breast cancer survivors: A prospective population-based patient cohort study.

    abstract::More women are surviving after breast cancer due to early detection and modern treatment strategies. Body weight also influences survival. We aimed to characterize associations between postdiagnosis weight change and prognosis in postmenopausal long-term breast cancer survivors. We used data from a prospective populat...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Jung AY,Hüsing A,Behrens S,Krzykalla J,Obi N,Becher H,Chang-Claude J

    更新日期:2021-01-01 00:00:00

  • Relationship of tumor-specific transplantation antigens to the histocompatibility complex: dissociation of in vitro alloantigen expression and in vivo alloimmunity from tumor-specific transplantation antigen strength.

    abstract::The studies reported here explore the relationship between tumor-specific transplantation antigens (TSTA) and (1) the expression of serologically defined specificities, and (2) the immunogenicity of H-2K- or H-2D-determined alloantigens on methylcholanthrene (MCA)-induced murine fibrosarcomas. Expression of H-2K and H...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Chauvenet PH,Smith RT

    更新日期:1978-07-15 00:00:00

  • Tissue and serum metabolomic phenotyping for diagnosis and prognosis of hepatocellular carcinoma.

    abstract::More than two-thirds of patients with hepatocellular carcinoma (HCC) cannot receive curative therapy and have poor survival due to late diagnosis and few prognostic directions. In our study, nontargeted and targeted metabolomics analyses were conducted by liquid chromatography-mass spectrometry to characterize metabol...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Han J,Han ML,Xing H,Li ZL,Yuan DY,Wu H,Zhang H,Wang MD,Li C,Liang L,Song YY,Xu AJ,Wu MC,Shen F,Xie Y,Yang T

    更新日期:2020-03-15 00:00:00

  • In vivo growth inhibition of L1210 leukemia by 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A), a new inhibitor of S-adenosylmethionine decarboxylase.

    abstract::We studied the in vivo growth-inhibitory effect of the new S-adenosylmethionine decarboxylase inhibitor 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A). L1210-bearing DBA-2 mice were treated with increasing CGP 48664A doses from 1 day after i.p. L1210 cell inoculation. Treatment was continued for 4 days, after w...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Dorhout B,Te Velde RJ,Ferwerda H,Kingma AW,De Hoog E,Muskiet FA

    更新日期:1995-04-10 00:00:00

  • Cell-mediated mutagenesis in cultured Chinese hamster cells by polycyclic hydrocarbons: mutagenicity and DNA reaction related to carcinogenicity in a series of compounds.

    abstract::Three polycyclic hydrocarbons, benz(a)anthracene, 3-methylcholanthrene and 7,12-dimethylbenz(a)anthracene, have been studied in a cell-mediated mutagenesis system using BHK 21 cells to metabolize the hydrocarbons and V-79 cells as targets for detecting induced cytotoxicity and mutation. In large-scale experiments, the...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Wigley CB,Newbold RF,Amos J,Brookes P

    更新日期:1979-05-15 00:00:00

  • Risk of invasive cervical cancer in relation to clinical investigation and treatment after abnormal cytology: a population-based case-control study.

    abstract::A substantial proportion of women with cervical cancer that have participated in cervical screening have a history of an abnormal cytology result. Our objective was to assess the impact of histological investigation and treatment of women with abnormal cytology on the subsequent risk of invasive cervical cancer. All i...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Silfverdal L,Kemetli L,Sparén P,Andrae B,Strander B,Ryd W,Dillner J,Törnberg S

    更新日期:2011-09-15 00:00:00

  • Qualitative and quantitative differences between Burkitt lymphoma and lymphoblastoid cell lines in the expression of membrane ecto-nucleotidases and in the response to agonists of the A2-type adenosine receptor.

    abstract::The activity of ecto-nucleotidases has been determined on intact cells from Burkitt lymphoma (BL) and lymphoblastoid cell lines established in vitro (LCLs). BL cells never express ecto-5'-nucleotidase (5'-N) and exhibit only low levels of ecto-ATPase activity, whereas LCL-cells usually express both enzymes to varying ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Gutensohn W,Jahn H

    更新日期:1988-03-15 00:00:00

  • IGFBP7 downregulation is associated with tumor progression and clinical outcome in hepatocellular carcinoma.

    abstract::Insulin-like growth factor-binding protein 7 (IGFBP7) functions in several cellular processes including proliferation, senescence and apoptosis. This study analyzed IGFBP7 function in hepatocellular carcinoma (HCC) cells by gene manipulation and investigated the prognostic significance of IGFBP7 expression in clinical...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Tomimaru Y,Eguchi H,Wada H,Kobayashi S,Marubashi S,Tanemura M,Umeshita K,Kim T,Wakasa K,Doki Y,Mori M,Nagano H

    更新日期:2012-01-15 00:00:00

  • Variant estrogen receptor alpha mRNAs in human breast cancer specimens.

    abstract::A panel of human breast cancer specimens was examined for single base change mutations by DNA sequencing and for larger deletions using a PCR-based assay. In the cancer specimens examined, no sequencing variants were detected other than a previously characterized polymorphism. Although most of the specimens contained ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Anandappa SY,Sibson R,Platt-Higgins A,Winstanley JH,Rudland PS,Barraclough R

    更新日期:2000-10-15 00:00:00

  • Progress against cancer in the Netherlands since the late 1980s: an epidemiological evaluation.

    abstract::Progress against cancer through prevention and treatment is often measured by survival statistics only instead of analyzing trends in incidence, survival and mortality simultaneously because of interactive influences. This study combines these parameters of major cancers to provide an overview of the progress achieved...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Karim-Kos HE,Kiemeney LA,Louwman MW,Coebergh JW,de Vries E

    更新日期:2012-06-15 00:00:00

  • Differential inducibility of Epstein-Barr virus in cloned, non-producer Raji cells.

    abstract::Cells of the human lymphoblastoid non-producer line Raji were cloned in soft agar. Individual colonies were isolated and analyzed for their inducibility of the Epstein-Barr virus-associated early antigen (EA). The induction of EA by the tumor promoter TPA varied among the different cell clones. Clones with very high a...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Bister K,Yamamoto N,zur Hausen H

    更新日期:1979-06-15 00:00:00

  • BRACHYURY confers cancer stem cell characteristics on colorectal cancer cells.

    abstract::Cancer stem cells (CSCs) are initiating cells in colorectal cancer (CRC). Colorectal tumours undergo epithelial to mesenchymal transition (EMT)-like processes at the invasive front, enabling invasion and metastasis, and recent studies have linked this process to the acquisition of stem cell-like properties. It is of f...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Sarkar D,Shields B,Davies ML,Müller J,Wakeman JA

    更新日期:2012-01-15 00:00:00

  • DNA methylation age as a biomarker for cancer.

    abstract::Cancer is well established as an age-associated disease, and there is substantial overlap in the molecular, cellular and physiological changes observed with both ageing and the progression of cancer. Age-specific declines in resilience mechanisms such as DNA repair or epigenetic maintenance may contribute to the devel...

    journal_title:International journal of cancer

    pub_type: 杂志文章,评审


    authors: Lau CE,Robinson O

    更新日期:2021-01-04 00:00:00

  • Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through upregulation of cathepsin B.

    abstract::Invasiveness is one of the key features of aggressive prostate cancer; however, our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype through downstream eff...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Beckham TH,Lu P,Cheng JC,Zhao D,Turner LS,Zhang X,Hoffman S,Armeson KE,Liu A,Marrison T,Hannun YA,Liu X

    更新日期:2012-11-01 00:00:00

  • CB694, a novel antimitotic with antitumor activities.

    abstract::During the course of a mechanism-based screening program aimed at identifying new antimitotic agents, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, was identified. The compound, designated CB694, caused inhibition of proliferation of a wide range...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Weiderhold KN,Randall-Hlubek DA,Polin LA,Hamel E,Mooberry SL

    更新日期:2006-02-15 00:00:00

  • Coffee consumption and risk of endometrial cancer: a prospective study in Japan.

    abstract::Coffee has been proposed to decrease the circulating insulin and estrogen levels, which are related to the development of endometrial cancer. However, few studies have prospectively assessed the association between coffee consumption and endometrial cancer. We conducted a population-based prospective cohort study in 5...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Shimazu T,Inoue M,Sasazuki S,Iwasaki M,Kurahashi N,Yamaji T,Tsugane S,JPHC Study Group Members of the Japan Public Health Center-based Prospective Study.

    更新日期:2008-11-15 00:00:00

  • DNA adducts in urothelial cells: relationship with biomarkers of exposure to arylamines and polycyclic aromatic hydrocarbons from tobacco smoke.

    abstract::Markers of exposure to polycyclic aromatic hydrocarbons (urinary 1-hydroxypyrene-glucuronide) and aromatic amines (4-aminobiphenyl-hemoglobin adducts), as well as urinary mutagenicity, were measured in 47 healthy smokers and 50 nonsmokers. DNA adducts were determined by P32-postlabeling in the exfoliated bladder cells...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Vineis P,Talaska G,Malaveille C,Bartsch H,Martone T,Sithisarankul P,Strickland P

    更新日期:1996-01-26 00:00:00

  • Differential survival of γδT cells, αβT cells and NK cells upon engagement of NKG2D by NKG2DL-expressing leukemic cells.

    abstract::Herein, we show that γδT, CD8(+) αβT lymphocytes and natural killer (NK) cells display a different sensitivity to survival signals delivered via NKG2D surface receptor. All the three effector cell populations activate Akt1/PKBalpha through the engagement of this molecule. Upon binding to leukemic cells expressing NKG2...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Poggi A,Zancolli M,Boero S,Catellani S,Musso A,Zocchi MR

    更新日期:2011-07-15 00:00:00

  • A phospholipase D and protein kinase C inhibitor blocks the spreading of murine mammary adenocarcinoma cells altering f-actin and beta1-integrin point contact distribution.

    abstract::Spreading is a critical process involved in motility and growth of tumor cells during the metastatic cascade. Focal adhesion kinase, src-proteins and PKC have been reported to participate in the regulation of cytoskeleton organization in both normal and transformed cells during spreading. The role of other signaling e...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Aguirre Ghiso JA,Farías EF,Alonso DF,Arregui C,Bal de Kier Joffé E

    更新日期:1997-05-29 00:00:00

  • galectin-1 and galectin-3 expression in human bladder transitional-cell carcinomas.

    abstract::Galectin-1 and galectin-3 are galactoside-binding proteins involved in different steps of tumor progression and potential targets for therapy. We have investigated the expression of these galectins in 38 human bladder transitional-cell carcinomas of different histological grade and clinical stage and in 5 normal uroth...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Cindolo L,Benvenuto G,Salvatore P,Pero R,Salvatore G,Mirone V,Prezioso D,Altieri V,Bruni CB,Chiariotti L

    更新日期:1999-02-19 00:00:00

  • Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer.

    abstract::Family history (FH) of lung cancer is an established risk factor for lung cancer, but the modifying effect of smoking in relatives has been rarely examined. Also, the role of FH of nonmalignant lung diseases on lung cancer risk is not well known. We examined the role of FH of cancer and nonmalignant lung diseases in l...

    journal_title:International journal of cancer

    pub_type: 杂志文章,随机对照试验


    authors: Gao Y,Goldstein AM,Consonni D,Pesatori AC,Wacholder S,Tucker MA,Caporaso NE,Goldin L,Landi MT

    更新日期:2009-07-01 00:00:00

  • Treatment of oral leukoplakia with a low-dose of beta-carotene and vitamin C supplements: a randomized controlled trial.

    abstract::Management of oral leukoplakia-a potentially malignant disorder-is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combine...

    journal_title:International journal of cancer

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Nagao T,Warnakulasuriya S,Nakamura T,Kato S,Yamamoto K,Fukano H,Suzuki K,Shimozato K,Hashimoto S

    更新日期:2015-04-01 00:00:00

  • Variation in promptness of presentation among 10,297 patients subsequently diagnosed with one of 18 cancers: evidence from a National Audit of Cancer Diagnosis in Primary Care.

    abstract::Cancer awareness public campaigns aim to shorten the interval between symptom onset and presentation to a doctor (the 'patient interval'). Appreciating variation in promptness of presentation can help to better target awareness campaigns. We explored variation in patient intervals recorded in consultations with genera...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Keeble S,Abel GA,Saunders CL,McPhail S,Walter FM,Neal RD,Rubin GP,Lyratzopoulos G

    更新日期:2014-09-01 00:00:00