The role of kinesin family proteins in tumorigenesis and progression

The kinesin superfamily contains a conserved class of microtubule‐dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene‐related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer‐targeted therapy involving the kinesin family proteins. Cancer 2010. © 2010 American Cancer Society.

[1]  D. Benayahu,et al.  The Regulation of MS-KIF18A Expression and Cross Talk with Estrogen Receptor , 2009, PloS one.

[2]  J. Paris,et al.  Cloning by differential screening of a Xenopus cDNA that encodes a kinesin-related protein , 1991, Molecular and cellular biology.

[3]  K. Mimori,et al.  Mitotic centromere-associated kinesin is a novel marker for prognosis and lymph node metastasis in colorectal cancer , 2008, British Journal of Cancer.

[4]  B. McEwen,et al.  CENP-E is essential for reliable bioriented spindle attachment, but chromosome alignment can be achieved via redundant mechanisms in mammalian cells. , 2001, Molecular biology of the cell.

[5]  Michael P. Sheetz,et al.  Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility , 1985, Cell.

[6]  W. Kaelin,et al.  The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. , 2005, Biochemical and biophysical research communications.

[7]  James Briscoe,et al.  The Kinesin Protein Kif7 Is a Critical Regulator of Gli Transcription Factors in Mammalian Hedgehog Signaling , 2009, Science Signaling.

[8]  J. Inoue,et al.  Kid, a novel kinesin‐like DNA binding protein, is localized to chromosomes and the mitotic spindle. , 1996, The EMBO journal.

[9]  L. Goldstein,et al.  CENP-E Is a Plus End–Directed Kinetochore Motor Required for Metaphase Chromosome Alignment , 1997, Cell.

[10]  Fabien Calvo,et al.  Distinct expression patterns of the E3 ligase SIAH-1 and its partner Kid/KIF22 in normal tissues and in the breast tumoral processes , 2010, Journal of experimental & clinical cancer research : CR.

[11]  P. Jallepalli,et al.  Chromosome segregation and cancer: cutting through the mystery , 2001, Nature Reviews Cancer.

[12]  T. Kapoor,et al.  Chromosomes Can Congress to the Metaphase Plate Before Biorientation , 2006, Science.

[13]  Timothy J. Mitchison,et al.  Kin I Kinesins Are Microtubule-Destabilizing Enzymes , 1999, Cell.

[14]  Tomoatsu Hayashi,et al.  Role of the Kinesin-2 Family Protein, KIF3, during Mitosis* , 2006, Journal of Biological Chemistry.

[15]  Gerd Ritter,et al.  Immunotherapeutic Targets Cancer : Identification of Potential Diagnostic and Cancer-related Serological Recognition of Human Colon Updated , 2002 .

[16]  H. Kato,et al.  Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy. , 2006, Lung cancer.

[17]  K. Lukong,et al.  Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration. , 2008, Cellular signalling.

[18]  Lesley N. Weaver,et al.  Kinesin-14 family proteins HSET/XCTK2 control spindle length by cross-linking and sliding microtubules. , 2009, Molecular biology of the cell.

[19]  T. Misteli,et al.  Tumor Formation via Loss of a Molecular Motor Protein , 2006, Current Biology.

[20]  T. Corson,et al.  KIF14 Messenger RNA Expression Is Independently Prognostic for Outcome in Lung Cancer , 2007, Clinical Cancer Research.

[21]  M. Teh,et al.  FOXM1 is a downstream target of Gli1 in basal cell carcinomas. , 2002, Cancer research.

[22]  N. Hirokawa,et al.  Point mutation of adenosine triphosphate-binding motif generated rigor kinesin that selectively blocks anterograde lysosome membrane transport , 1995, The Journal of cell biology.

[23]  J. Bertoglio,et al.  CUX1 and E2F1 Regulate Coordinated Expression of the Mitotic Complex Genes Ect2, MgcRacGAP, and MKLP1 in S Phase , 2008, Molecular and Cellular Biology.

[24]  G. Pigino,et al.  JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport , 2006, Nature Neuroscience.

[25]  J. Shabanowitz,et al.  Aurora B Phosphorylates Centromeric MCAK and Regulates Its Localization and Microtubule Depolymerization Activity , 2004, Current Biology.

[26]  D. Huszar,et al.  Kinesin motor proteins as targets for cancer therapy , 2009, Cancer and Metastasis Reviews.

[27]  N. Nakamura,et al.  A Novel Kinesin‐Like Protein, KIF1Bβ3 Is Involved in the Movement of Lysosomes to the Cell Periphery in Non‐Neuronal Cells , 2004, Traffic.

[28]  M. K. Cooper,et al.  Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival , 2009, Oncogene.

[29]  Stefan Hümmer,et al.  The Human Kinesin Kif18A Is a Motile Microtubule Depolymerase Essential for Chromosome Congression , 2007, Current Biology.

[30]  Cristina Montagna,et al.  Aneuploidy acts both oncogenically and as a tumor suppressor. , 2007, Cancer cell.

[31]  M. Takagi,et al.  Importin-β and the small guanosine triphosphatase Ran mediate chromosome loading of the human chromokinesin Kid , 2008, The Journal of cell biology.

[32]  Tetsu Akiyama,et al.  Identification of a link between the tumour suppressor APC and the kinesin superfamily , 2002, Nature Cell Biology.

[33]  T. Tsunoda,et al.  Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. , 2001, Cancer research.

[34]  Bin Liu,et al.  Reduced expression of cenp-e in human hepatocellular carcinoma , 2009, Journal of experimental & clinical cancer research : CR.

[35]  H. Vogel,et al.  CHD5 Is a Tumor Suppressor at Human 1p36 , 2007, Cell.

[36]  H. Moch,et al.  Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL , 2003, Nature.

[37]  G. Stark,et al.  Overexpression of kinesins mediates docetaxel resistance in breast cancer cells. , 2009, Cancer research.

[38]  R. Shiekhattar,et al.  The Motor Protein Kinesin-1 Links Neurofibromin and Merlin in a Common Cellular Pathway of Neurofibromatosis* , 2002, The Journal of Biological Chemistry.

[39]  M. Justice,et al.  Overexpression of Eg5 causes genomic instability and tumor formation in mice. , 2007, Cancer research.

[40]  Timothy W Corson,et al.  KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers , 2005, Oncogene.

[41]  Linda Wordeman,et al.  The kinesin-8 motor Kif18A suppresses kinetochore movements to control mitotic chromosome alignment. , 2008, Developmental cell.

[42]  N. Hirokawa,et al.  All kinesin superfamily protein, KIF, genes in mouse and human , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Russell L. Malmberg,et al.  A standardized kinesin nomenclature , 2004, The Journal of cell biology.

[44]  W. Sterry,et al.  Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling , 2006, Molecular Cancer.

[45]  E. Voest,et al.  Mobility of the von Hippel-Lindau tumour suppressor protein is regulated by kinesin-2. , 2008, Experimental cell research.

[46]  N. Hirokawa,et al.  Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. , 2001, Cell.

[47]  Shuichi Tsutsumi,et al.  Global gene expression analysis of gastric cancer by oligonucleotide microarrays. , 2002, Cancer research.

[48]  N. Hirokawa,et al.  Cloning and characterization of KAP3: a novel kinesin superfamily-associated protein of KIF3A/3B. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  K. Basso,et al.  Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: Identification of candidate amplified and overexpressed genes , 2007, Genes, chromosomes & cancer.

[50]  Jesper Nylandsted,et al.  Depletion of Kinesin 5B Affects Lysosomal Distribution and Stability and Induces Peri-Nuclear Accumulation of Autophagosomes in Cancer Cells , 2009, PloS one.

[51]  Mogens Kruhøffer,et al.  Gene Expression in the Urinary Bladder , 2004, Cancer Research.

[52]  G. Bloom,et al.  Submolecular domains of bovine brain kinesin identified by electron microscopy and monoclonal antibody decoration , 1989, Cell.

[53]  Nobutaka Hirokawa,et al.  Analysis of the kinesin superfamily: insights into structure and function. , 2005, Trends in cell biology.

[54]  M. Follettie,et al.  Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. , 2005, Cancer research.

[55]  Yun Zheng,et al.  CENP-E forms a link between attachment of spindle microtubules to kinetochores and the mitotic checkpoint , 2000, Nature Cell Biology.

[56]  Nobutaka Hirokawa,et al.  Kinesin Transports RNA Isolation and Characterization of an RNA-Transporting Granule , 2004, Neuron.

[57]  Toru Nakamura,et al.  A unique gene having homology with the kinesin family member 18A encodes a tumour-associated antigen recognised by cytotoxic T lymphocytes from HLA-A2+ colon cancer patients. , 2005, European journal of cancer.

[58]  A. Ligon,et al.  A germline mutation of the KIF1Bβ gene on 1p36 in a family with neural and nonneural tumors , 2008, Human Genetics.

[59]  L. Goldstein,et al.  The road less traveled: emerging principles of kinesin motor utilization. , 1999, Annual review of cell and developmental biology.

[60]  Yusuke Nakamura,et al.  Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer , 2007, Clinical Cancer Research.

[61]  Min Liu,et al.  Parkin Regulates Eg5 Expression by Hsp70 Ubiquitination-dependent Inactivation of c-Jun NH2-terminal Kinase* , 2008, Journal of Biological Chemistry.

[62]  Y. Toyoshima,et al.  Cdc2‐mediated phosphorylation of Kid controls its distribution to spindle and chromosomes , 2003, The EMBO journal.

[63]  D. Benayahu,et al.  New insights on cellular distribution, microtubule interactions and post‐translational modifications of MS‐KIF18A , 2008, Journal of cellular physiology.

[64]  M. Meyerson,et al.  The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. , 2008, Genes & development.

[65]  D. Pellman,et al.  Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. , 2008, Genes & development.

[66]  N. Hirokawa,et al.  Kinesin superfamily motor proteins and intracellular transport , 2009, Nature Reviews Molecular Cell Biology.

[67]  M. Brandeis,et al.  Human Kid is Degraded by the APC/CCdh1 but Not by the APC/CCdc20 , 2007, Cell cycle.

[68]  B. Boman,et al.  Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. , 2001, Cancer research.

[69]  B. Schaar,et al.  CENP-E Function at Kinetochores Is Essential for Chromosome Alignment , 1997, The Journal of cell biology.

[70]  Z. Bonday,et al.  Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss , 2003, The Journal of cell biology.

[71]  T. Misteli,et al.  Human chromokinesin KIF4A functions in chromosome condensation and segregation , 2004, The Journal of cell biology.

[72]  Yusuke Nakamura,et al.  Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell. , 2005, Cancer research.

[73]  J. Snyder,et al.  Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function , 2007, Molecular Cancer Therapeutics.

[74]  T. Corson,et al.  KIF14 mRNA expression is a predictor of grade and outcome in breast cancer , 2006, International journal of cancer.

[75]  Shridar Ganesan,et al.  X chromosomal abnormalities in basal-like human breast cancer. , 2006, Cancer cell.

[76]  Peter S. Linsley,et al.  RNA Interference-Mediated Silencing of Mitotic Kinesin KIF14 Disrupts Cell Cycle Progression and Induces Cytokinesis Failure , 2006, Molecular and Cellular Biology.

[77]  Marina Bibikova,et al.  Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. , 2005, Molecular biology of the cell.

[78]  K. McKim,et al.  Kinesin 6 family member Subito participates in mitotic spindle assembly and interacts with mitotic regulators , 2006, Journal of Cell Science.

[79]  N. Hirokawa,et al.  KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria , 1994, Cell.

[80]  W. R. Bishop,et al.  Farnesyl Transferase Inhibitors Block the Farnesylation of CENP-E and CENP-F and Alter the Association of CENP-E with the Microtubules* , 2000, The Journal of Biological Chemistry.

[81]  N. Hirokawa,et al.  The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium , 2005, Nature Cell Biology.

[82]  D. Compton,et al.  The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles , 2001, The Journal of cell biology.

[83]  Erich A. Nigg,et al.  KIF14 and citron kinase act together to promote efficient cytokinesis , 2006, The Journal of cell biology.

[84]  Min Liu,et al.  Inhibition of the Mitotic Kinesin Eg5 Up-regulates Hsp70 through the Phosphatidylinositol 3-Kinase/Akt Pathway in Multiple Myeloma Cells* , 2006, Journal of Biological Chemistry.

[85]  J. Mackay,et al.  The C-terminal region of the stalk domain of ubiquitous human kinesin heavy chain contains the binding site for kinesin light chain. , 1998, Biochemistry.

[86]  M. Krawczak,et al.  Different combinations of biallelic APC mutation confer different growth advantages in colorectal tumours. , 2002, Cancer research.

[87]  N. Hirokawa,et al.  Targeted Disruption of Mouse Conventional Kinesin Heavy Chain kif5B, Results in Abnormal Perinuclear Clustering of Mitochondria , 1998, Cell.

[88]  Y. Mao,et al.  Activating and Silencing the Mitotic Checkpoint through CENP-E-Dependent Activation/Inactivation of BubR1 , 2003, Cell.

[89]  Jeanne A. Ferguson,et al.  Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). , 2009, Journal of medicinal chemistry.

[90]  Yusuke Nakamura,et al.  Involvement of kinesin family member 2C/mitotic centromere‐associated kinesin overexpression in mammary carcinogenesis , 2007, Cancer science.

[91]  Y. Toyoshima,et al.  The human chromokinesin Kid is a plus end‐directed microtubule‐based motor , 2003, The EMBO journal.

[92]  Min Liu,et al.  Validating the mitotic kinesin Eg5 as a therapeutic target in pancreatic cancer cells and tumor xenografts using a specific inhibitor. , 2008, Biochemical pharmacology.

[93]  N. Hirokawa,et al.  Kinesin and dynein superfamily proteins and the mechanism of organelle transport. , 1998, Science.

[94]  K. Mimori,et al.  Clinicopathological and biological significance of mitotic centromere-associated kinesin overexpression in human gastric cancer , 2007, British Journal of Cancer.

[95]  Young Ho Kim,et al.  Regulation of the human mitotic centromere-associated kinesin (MCAK) promoter by the transcription factors Sp1 and E2F1. , 2008, Biochimica et biophysica acta.

[96]  N. Hirokawa,et al.  Charcot-Marie-Tooth Disease Type 2A Caused by Mutation in a Microtubule Motor KIF1Bβ , 2001, Cell.