The therapeutic potential of targeting the cell cycle.

With the advent of modern molecular genetics, molecular biology and biochemistry has come a revolution in oncology drug discovery research. We are rapidly developing an increased understanding in the mechanisms driving cellular proliferation, transformation, differentiation and metastasis. The hope is that from these advances will emerge novel therapeutics that are more specific, more efficacious and less toxic than their predecessors. Uncontrolled proliferation is a hallmark of a cancer cell. Over the past two decades it has become increasingly clear that molecules that directly control cell cycle progression accumulate defects during tumourigenesis. These defects can result in the loss of checkpoint control and/or the inappropriate activation of the 'drivers' of cell cycle progression, the cyclin-dependent kinases (cdks). This review will describe the recent advances in our understanding of cell cycle regulation and its relation to tumourigenesis, and highlight the potential for the development of novel anticancer therapeutics.

[1]  E. Sausville,et al.  Early Induction of Apoptosis in Hematopoietic Cell Lines After Exposure to Flavopiridol , 1998 .

[2]  Y. Nouvian‐Dooghe,et al.  Human cyclin B1 is targeted to the nucleus in G1 phase prior to its accumulation in the cytoplasm. , 1996, Oncogene.

[3]  S. Bursell,et al.  Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC β Inhibitor , 1996, Science.

[4]  E. Lees,et al.  Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. , 1996, Oncogene.

[5]  L. Chin,et al.  Role of the INK4a Locus in Tumor Suppression and Cell Mortality , 1996, Cell.

[6]  F. Lallemand,et al.  Effects of olomoucine, a selective inhibitor of cyclin-dependent kinases, on cell cycle progression in human cancer cell lines. , 1997, Anti-cancer drugs.

[7]  H. Yokozaki,et al.  Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas , 1995, International journal of cancer.

[8]  Erich A. Nigg,et al.  Cellular substrates of p34cdc2 and its companion cyclin-dependent kinases , 1993 .

[9]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[10]  B. Franza,et al.  cdc2 phosphorylation is required for its interaction with cyclin. , 1991 .

[11]  Herman Yeger,et al.  Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer , 1997, Nature Medicine.

[12]  Emma Lees,et al.  Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice , 1994, Nature.

[13]  Peter A. Jones,et al.  P16 gene in uncultured tumours , 1994, Nature.

[14]  E. Harlow,et al.  Identification of G1 kinase activity for cdk6, a novel cyclin D partner , 1994, Molecular and cellular biology.

[15]  S H Kim,et al.  Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Loda,et al.  The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. , 1997, Cancer research.

[17]  H. Yokozaki,et al.  Overexpression of Cyclin‐dependent Kinase‐activating CDC25B Phosphatase in Human Gastric Carcinomas , 1997, Japanese journal of cancer research : Gann.

[18]  C. Boshoff,et al.  The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1 , 1997, Journal of virology.

[19]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[20]  S. Matsushita,et al.  Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. , 1984, Science.

[21]  Stephen J. Elledge,et al.  p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest , 1994, Cell.

[22]  R. Weinberg,et al.  Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. , 1994, Genes & development.

[23]  S H Kim,et al.  Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. , 1997, European journal of biochemistry.

[24]  R. Bernards,et al.  CDK-Independent Activation of Estrogen Receptor by Cyclin D1 , 1997, Cell.

[25]  M. Ogawa,et al.  Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas. , 1994, Biochemical and biophysical research communications.

[26]  A. Iolascon,et al.  Homozygous deletions of cyclin-dependent kinase inhibitor genes, p16(INK4A) and p18, in childhood T cell lineage acute lymphoblastic leukemias. , 1996, Leukemia.

[27]  H. Yokozaki,et al.  Frequent Amplification of the Cyclin E Gene in Human Gastric Carcinomas , 1995, Japanese journal of cancer research : Gann.

[28]  S. Reed,et al.  Cyclin E-induced S phase without activation of the pRb/E2F pathway. , 1997, Genes & development.

[29]  Y. Xiong,et al.  Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. , 1994, Oncogene.

[30]  L Meijer,et al.  Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. , 1997, European journal of biochemistry.

[31]  Carl W. Miller,et al.  Alterations of CDKN2 (p16) in non‐small cell lung cancer , 1995, Genes, chromosomes & cancer.

[32]  J. Ahomadégbé,et al.  Topoisomerase II-mediated DNA cleavage activity induced by ellipticines on the human tumor cell line N417. , 1989, Biochemical pharmacology.

[33]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[34]  K. Kinzler,et al.  p21 is necessary for the p53-mediated G1 arrest in human cancer cells. , 1995, Cancer research.

[35]  S. Hinrichs,et al.  Structural evidence for the authenticity of the human retinoblastoma gene. , 1987, Science.

[36]  R. Weinberg,et al.  A cyclin associated with the CDK-activating kinase MO15 , 1994, Nature.

[37]  L. Hartwell,et al.  Checkpoints: controls that ensure the order of cell cycle events. , 1989, Science.

[38]  Steven K. Hanks,et al.  Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins , 1992, Cell.

[39]  A. Arnold The cyclin D1/PRAD1 oncogene in human neoplasia. , 1995, Journal of investigative medicine : the official publication of the American Federation for Clinical Research.

[40]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[41]  Seung Ki Lee,et al.  A Specific Inhibitor of Cyclin-dependent Protein Kinases, CDC2 and CDK2 , 1996, Molecules and Cells.

[42]  Marc W. Kirschner,et al.  How Proteolysis Drives the Cell Cycle , 1996, Science.

[43]  D. Demetrick,et al.  Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. , 1994, Cytogenetics and cell genetics.

[44]  S. Kaufmann,et al.  Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. , 1996, Cancer research.

[45]  M. Barinaga A new twist to the cell cycle. , 1995, Science.

[46]  E. Sausville,et al.  Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. , 1992, Journal of the National Cancer Institute.

[47]  A. Rustgi,et al.  p16 inhibition of transformed and primary squamous epithelial cells. , 1996, Oncogene.

[48]  C. Bréchot,et al.  Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma , 1990, Nature.

[49]  S. Mori,et al.  Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. , 1994, Cancer research.

[50]  Marc W. Kirschner,et al.  cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2 , 1991, Cell.

[51]  David M. Livingston,et al.  Functional interactions of the retinoblastoma protein with mammalian D-type cyclins , 1993, Cell.

[52]  M. Merino,et al.  Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions , 1995, Nature Medicine.

[53]  M. Serrano,et al.  A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma , 1995, Science.

[54]  L Meijer,et al.  Multiple modes of ligand recognition: Crystal structures of cyclin‐dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine , 1995, Proteins.

[55]  Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p21WAF1 , 1997, Current Biology.

[56]  A. N. Meyer,et al.  Nuclear localization of cyclin B1 mediates its biological activity and is regulated by phosphorylation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[57]  A. Giordano,et al.  A Unique Domain of pRb2/p130 Acts as an Inhibitor of Cdk2 Kinase Activity* , 1997, The Journal of Biological Chemistry.

[58]  Jiri Bartek,et al.  Cyclin D1 protein expression and function in human breast cancer , 1994, International journal of cancer.

[59]  R. Weinberg,et al.  Function of a human cyclin gene as an oncogene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[60]  W. Lee,et al.  Human retinoblastoma susceptibility gene: cloning, identification, and sequence , 1987, Science.

[61]  R. Eddy,et al.  Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. , 1989, The Journal of clinical investigation.

[62]  A. Harris,et al.  Inactivation of Cdc2 increases the level of apoptosis induced by DNA damage. , 1995, Journal of cell science.

[63]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[64]  A. Kumagai,et al.  Purification and Molecular Cloning of Plx1, a Cdc25-Regulatory Kinase from Xenopus Egg Extracts , 1996, Science.

[65]  James M. Roberts,et al.  Cyclin E-CDK2 is a regulator of p27Kip1. , 1997, Genes & development.

[66]  N. Saijo,et al.  Effect of suramin on p34cdc2 kinase in vitro and in extracts from human H69 cells: evidence for a double mechanism of action. , 1994, Biochemical and biophysical research communications.

[67]  S. Reed,et al.  Isolation of three novel human cyclins by rescue of G1 cyclin (cln) function in yeast , 1991, Cell.

[68]  James M. Roberts,et al.  Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. , 1995, Cancer research.

[69]  J. Bartek,et al.  Cell cycle analysis of the activity, subcellular localization, and subunit composition of human CAK (CDK-activating kinase) , 1994, The Journal of cell biology.

[70]  R. Eeles,et al.  Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression. , 1995, The American journal of pathology.

[71]  G. Landberg,et al.  Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein , 1997, Oncogene.

[72]  S. Lelièvre,et al.  Suramin is an inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[73]  R. Maestro,et al.  Overexpression of CDC25A and CDC25B in head and neck cancers. , 1997, Cancer research.

[74]  Sung-Hou Kim,et al.  Crystal structure of cyclin-dependent kinase 2 , 1993, Nature.

[75]  A Joly,et al.  CVT-313, a Specific and Potent Inhibitor of CDK2 That Prevents Neointimal Proliferation* , 1997, The Journal of Biological Chemistry.

[76]  E. Karsenti,et al.  Activation of the phosphatase activity of human cdc25A by a cdk2‐cyclin E dependent phosphorylation at the G1/S transition. , 1994, The EMBO journal.

[77]  R. Naik,et al.  An antiinflammatory cum immunomodulatory piperidinylbenzopyranone from dysoxylum binectariferum : isolation, structure and total synthesis , 1988 .

[78]  K. Kinzler,et al.  Deletion of p16 and p15 genes in brain tumors. , 1994, Cancer research.

[79]  S. Freer,et al.  Design of enzyme inhibitors using iterative protein crystallographic analysis. , 1991, Journal of medicinal chemistry.

[80]  A. Look,et al.  Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. , 1993, Cancer research.

[81]  C. Sheehan,et al.  The prognostic significance of p34cdc2 and cyclin D1 protein expression in prostate adenocarcinoma , 1997, Cancer.

[82]  R. Zeillinger,et al.  Cyclin gene amplification and overexpression in breast and ovarian cancers: Evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors , 1996, International journal of cancer.

[83]  B. Dynlacht,et al.  Specific regulation of E2F family members by cyclin-dependent kinases , 1997, Molecular and cellular biology.

[84]  P. Jeffrey,et al.  Structural basis of cyclin-dependent kinase activation by phosphorylation , 1996, Nature Structural Biology.

[85]  K Nasmyth,et al.  Viewpoint: Putting the Cell Cycle in Order , 1996, Science.

[86]  J. Bartek,et al.  Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16 , 1995, Nature.

[87]  R. DuBois,et al.  Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. , 1997, Cancer research.

[88]  M. Gossen,et al.  Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. , 1994, Molecular and cellular biology.

[89]  D. Beach,et al.  Activation of cdc2 protein kinase during mitosis in human cells: Cell cycle-dependent phosphorylation and subunit rearrangement , 1988, Cell.

[90]  L. Meijer,et al.  The effect of the cyclin-dependent kinase inhibitor olomoucine on cell cycle kinetics. , 1997, Experimental cell research.

[91]  K. Kinzler,et al.  p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. , 1995, Genes & development.

[92]  Tony Hunter,et al.  Isolation of a human cyclin cDNA: Evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2 , 1989, Cell.

[93]  P. Nurse Regulation of the eukaryotic cell cycle. , 1997, European journal of cancer.

[94]  F. C. Lucibello,et al.  Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E. , 1994, Oncogene.

[95]  G. Kong,et al.  Overexpression of cyclin D1 correlates with early recurrence in superficial bladder cancers. , 1997, British Journal of Cancer.

[96]  L. Hillis,et al.  Restenosis after successful coronary angioplasty. Pathophysiology and prevention. , 1988, The New England journal of medicine.

[97]  Daniel A. Gschwend,et al.  Molecular docking towards drug discovery , 1996, Journal of molecular recognition : JMR.

[98]  D. Bortner,et al.  Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E , 1997, Molecular and cellular biology.

[99]  Amanda G Paulovich,et al.  When Checkpoints Fail , 1997, Cell.

[100]  E. Sausville,et al.  Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[101]  James M. Roberts,et al.  Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. , 1996, Genes & development.

[102]  M. Loda,et al.  Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas , 1997, Nature Medicine.

[103]  M. Pagano,et al.  Cell cycle regulation by the ubiquitin pathway , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[104]  S. Hiebert Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression , 1993, Molecular and cellular biology.

[105]  R. Hruban,et al.  Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma , 1994, Nature Genetics.

[106]  G. Landberg,et al.  Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status. , 1996, British Journal of Cancer.

[107]  Ernest D. Laue,et al.  Structure of the cyclin-dependent kinase inhibitor p19Ink4d , 1997, Nature.

[108]  L. Meijer,et al.  Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. , 1997, Journal of medicinal chemistry.

[109]  E. Sugikawa,et al.  Inhibition of p53 Protein Phosphorylation by 9‐Hydroxyellipticine: A Possible Anticancer Mechanism , 1995, Japanese journal of cancer research : Gann.

[110]  H. Sedlacek,et al.  Antitumoral activity of flavone L-86-8275. , 1995, International journal of oncology.

[111]  N. Hayward,et al.  Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma , 1996, Nature Genetics.

[112]  E. Nabel,et al.  The p21 cyclin–dependent kinase inhibitor suppresses tumorigenicity in vivo , 1995, Nature Medicine.

[113]  K. G. Coleman,et al.  Identification of CDK4 Sequences Involved in Cyclin D1 and p16 Binding* , 1997, The Journal of Biological Chemistry.

[114]  K. A. McKenna,et al.  Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases. , 1996, Cancer research.

[115]  S. van den Heuvel,et al.  Distinct roles for cyclin-dependent kinases in cell cycle control. , 1993, Science.

[116]  S. Elledge,et al.  G1 cyclin-dependent kinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts , 1998, Current Biology.

[117]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[118]  P. Hajduk,et al.  NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein. , 1997, Journal of medicinal chemistry.

[119]  C. Moskaluk,et al.  Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. , 1997, Cancer research.

[120]  P. Pollock,et al.  Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds , 1997, Oncogene.

[121]  A. El‐Naggar,et al.  PRAD‐1 (CCND1)/Cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma , 1994, Cancer.

[122]  David O. Morgan,et al.  Principles of CDK regulation , 1995, Nature.

[123]  J. Takahara,et al.  UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene product in A549 human lung cancer cell line. , 1996, Biochemical and biophysical research communications.

[124]  E. Sausville,et al.  Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. , 1996, Cancer research.

[125]  T. Hunter,et al.  The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. , 1988, Science.

[126]  Tony Hunter,et al.  p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21 , 1994, Cell.

[127]  Andrew W. Murray,et al.  Cyclin synthesis drives the early embryonic cell cycle , 1989, Nature.

[128]  E. Schierenberg,et al.  Cellular effects of olomoucine, an inhibitor of cyclin‐dependent kinases , 1995, Biology of the cell.

[129]  A. Pardee,et al.  A restriction point for control of normal animal cell proliferation. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[130]  Bruno Amati,et al.  Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1 , 1997, The EMBO journal.

[131]  K. Keyomarsi,et al.  Redundant cyclin overexpression and gene amplification in breast cancer cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[132]  S. Kaufmann,et al.  Antineoplastic Agents: the Importance of Sequence of Administration' , 2022 .

[133]  R. Fåhraeus,et al.  Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide from p16CDKN2/INK4A , 1996, Current Biology.

[134]  J. Lapointe,et al.  A p18 mutant defective in CDK6 binding in human breast cancer cells. , 1996, Cancer research.

[135]  M. Ewen,et al.  Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4 , 1997, Molecular and cellular biology.

[136]  C. Sherr Cancer Cell Cycles , 1996, Science.

[137]  H. Yokozaki,et al.  Increased expression of p34cdc2 and its kinase activity in human gastric and colonic carcinomas , 1993, International journal of cancer.

[138]  M. Kitagawa,et al.  A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. , 1994, Oncogene.

[139]  J. Nevins,et al.  E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. , 1992, Science.

[140]  L. Ellis,et al.  The implications of angiogenesis for the biology and therapy of cancer metastasis , 1994, Cell.

[141]  R. Kerbel,et al.  Impact of the cyclin–dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents , 1996, Nature Medicine.

[142]  W. Ryder,et al.  Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. , 1996, British Journal of Cancer.

[143]  Stephen J. Elledge,et al.  Cell Cycle Checkpoints: Preventing an Identity Crisis , 1996, Science.

[144]  J. Bartek,et al.  Cell cycle‐related variation and tissue‐restricted expression of human cyclin D1 protein , 1994, The Journal of pathology.

[145]  A. Okuyama,et al.  MAP4 is the in vivo substrate for CDC2 kinase in HeLa cells: identification of an M-phase specific and a cell cycle-independent phosphorylation site in MAP4. , 1997, Biochemistry.

[146]  W. Zhou,et al.  A fumagillin derivative angiogenesis inhibitor, AGM-1470, inhibits activation of cyclin-dependent kinases and phosphorylation of retinoblastoma gene product but not protein tyrosyl phosphorylation or protooncogene expression in vascular endothelial cells. , 1994, Cancer research.

[147]  D. Beach,et al.  Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation. , 1995, Genes & development.

[148]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[149]  P. Nowell,et al.  Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. , 1984, Science.

[150]  James M. Roberts,et al.  Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients , 1997, Nature Medicine.

[151]  E. Lees,et al.  Cyclin E, a potential prognostic marker for breast cancer. , 1994, Cancer research.

[152]  Bert Vogelstein,et al.  Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 , 1996, Nature.

[153]  E. Sausville,et al.  Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. , 1994, Biochemical and biophysical research communications.

[154]  P. Anderson,et al.  Kinase cascades regulating entry into apoptosis , 1997, Microbiology and molecular biology reviews : MMBR.

[155]  H. Nguyen,et al.  Effects of cell cycle, wild-type p53 and DNA damage on p21CIP1/Waf1 expression in human breast epithelial cells. , 1995, Oncogene.

[156]  J. Slingerland,et al.  Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. , 1995, Oncogene.

[157]  R. Weinberg,et al.  Physical interaction of the retinoblastoma protein with human D cyclins , 1993, Cell.

[158]  P. Nurse,et al.  Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. , 1991, The EMBO journal.

[159]  Y. Shibata,et al.  p53-independent induction of apoptosis by cyclin-dependent kinase inhibition. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[160]  D. Fisher Apoptosis in cancer therapy: Crossing the threshold , 1994, Cell.

[161]  D. Sidransky,et al.  Rates of p16 (MTS1) mutations in primary tumors with 9p loss. , 1994, Science.

[162]  J. Blow,et al.  Inhibition of cyclin-dependent kinases by purine analogues. , 1994, European journal of biochemistry.

[163]  Kornelia Polyak,et al.  Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex , 1995, Nature.

[164]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[165]  Philip D. Jeffrey,et al.  Crystal structure of the p27Kip1 cyclin-dependent-kinase inibitor bound to the cyclin A–Cdk2 complex , 1996, Nature.

[166]  P. Beer-Romero,et al.  Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. , 1995, Science.

[167]  P. Wipf,et al.  A targeted library of small-molecule, tyrosine, and dual-specificity phosphatase inhibitors derived from a rational core design and random side chain variation. , 1997, Biochemistry.

[168]  M. Sporn,et al.  Recent advances in chemoprevention of cancer. , 1997, Science.

[169]  X. Liu,et al.  G1 control gene status is frequently altered in resectable non‐small cell lung cancer , 1997, International journal of cancer.

[170]  W. Clark,et al.  Germline p16 mutations in familial melanoma , 1994, Nature Genetics.

[171]  J. Leiden,et al.  Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty. , 1995, The Journal of clinical investigation.

[172]  M. Loda,et al.  CDC25 phosphatases as potential human oncogenes. , 1995, Science.

[173]  P. Hajduk,et al.  Discovering High-Affinity Ligands for Proteins: SAR by NMR , 1996, Science.

[174]  Stephen H. Friend,et al.  A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma , 1986, Nature.

[175]  M. Nagasawa,et al.  Rapid nuclear translocation and increased activity of cyclin-dependent kinase 6 after T cell activation. , 1997, Journal of immunology.

[176]  M. Skolnick,et al.  A cell cycle regulator potentially involved in genesis of many tumor types. , 1994, Science.

[177]  J. Gibbs,et al.  Pharmaceutical research in molecular oncology , 1994, Cell.

[178]  S. Shousha,et al.  High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. , 1997, Proceedings of the National Academy of Sciences of the United States of America.