The role of kinesin family proteins in tumorigenesis and progression: potential biomarkers and molecular targets for cancer therapy

Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Cancer (Impact Factor: 4.89). 11/2010; 116(22):5150-60. DOI: 10.1002/cncr.25461
Source: PubMed


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.

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Article: The role of kinesin family proteins in tumorigenesis and progression: potential biomarkers and molecular targets for cancer therapy

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    • "Although the role of c-MYC in cancer is well established [3], the role that Kinesin-1 plays in tumor formation is not well characterized. Kinesin-1 mRNA and protein levels are elevated in several tumor types and cancer cell lines [8]. Furthermore, ablation of KIF5B shows various degrees of cytotoxicity toward cancer cells [45]. "
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    ABSTRACT: c-MYC is an oncogenic transcription factor that is degraded by the proteasome pathway. However, the mechanism that regulates delivery of c-MYC to the proteasome for degradation is not well characterized. Here, the results show that the motor protein complex Kinesin-1 transports c-MYC to the cytoplasm for proteasomal degradation. Inhibition of Kinesin-1 function enhanced ubiquitination of c-MYC and induced aggregation of c-MYC in the cytoplasm. Transport studies showed that the c-MYC aggregates moved from the nucleus to the cytoplasm and KIF5B is responsible for the transport in the cytoplasm. Furthermore, inhibition of the proteasomal degradation process also resulted in an accumulation of c-MYC aggregates in the cytoplasm. Moreover, Kinesin-1 was shown to interact with c-MYC and the proteasome subunit S6a. Inhibition of Kinesin-1 function also reduced c-MYC-dependent transformation activities. Taken together, the results strongly suggest that Kinesin-1 transports c-MYC for proteasomal degradation in the cytoplasm and the proper degradation of c-MYC mediated by Kinesin-1 transport is important for transformation activities of c-MYC. In addition, the results indicate that Kinesin-1 transport mechanism is important for degradation of a number of other proteins as well.
    Biochimica et Biophysica Acta 05/2014; 1843(9). DOI:10.1016/j.bbamcr.2014.05.001 · 4.66 Impact Factor
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    • "Of these, mitosis is a complex and highly regulated process of eukaryotic cell division. Any exception in the process of mitosis will result in cell death, gene deletion, chromosome translocation, duplication and even carcinogenesis [12, 13]. "
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    ABSTRACT: Human hepatocellular carcinoma (HCC) is one of the most common fatal cancers and an important health problem worldwide, but its mechanism is still unclear. Microtubule (MT) kinesin motor proteins orchestrate a variety of cellular processes (e.g. mitosis, motility and organelle transportation) and have been involved in human carcinogenesis. KIF3B, the kinesin superfamily of proteins (KIFs), plays an important role in the regulation of mitotic progression. The expression of KIF3B and its involvement in HCC was investigated. Western blot and immunohistochemistry were used to measure the expression of KIF3B protein in HCC and adjacent non-tumorous tissues in 57 patients and Cell Counting Kit-8 to analyze the effects of growth and interference of KIF3B in the cell cycle process. KIF3B protein level was increased in HCC tissues compared with the adjacent non-tumorous tissues. It was significantly associated with histological differentiation, tumor size, the level of alpha fetal protein (AFP) and proliferation marker Ki-67. Over-expression of KIF3B was correlated with poor survival. Following release of HepG2 cells from serum starvation, the expression of KIF3B was up-regulated. Furthermore, suppression of KIF3B not only decreased cancer cell growth but also induced apoptosis of cells. Our results suggested that KIF3B expression was upregulated in HCC tumor tissues and proliferating HCC cells, and an increased KIF3B expression was associated with poor overall survival. KIF3B over-expression is involved in the pathogenesis of hepatocellular carcinoma and may serve as a potential therapeutic target for human HCC.
    Digestive Diseases and Sciences 12/2013; 59(4). DOI:10.1007/s10620-013-2969-2 · 2.61 Impact Factor
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    • "Although it has not been verified if the 3 0 -flanking region is essential for mimicking the endogenous expression pattern of KIF5Aa, it may be important for proper KIF5Aa tissue-specific expression, as reported previously (Tanaka et al., 2001). Errors in kinesin expression, as well as kinesin function, can result in cell death, cellular functional abnormalities, and cancer (Yu and Feng, 2010). This suggested a relationship between kinesin expression, tumorigenesis and cancer progression . "
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    ABSTRACT: Intracellular transport is spatiotemporally controlled by microtubule-dependent motor proteins, including kinesins. In order to elucidate the mechanisms controlling kinesin expression, it is important to analyze their genomic regulatory regions. In this study, we cloned the neuronal tissue-specific kinesin in medaka fish and generated transgenic fish which mimic endogenous neuronal kinesin expression in order to elucidate the mechanisms which regulate kinesin expression. Searches for medaka neuronal orthologues by RT-PCR identified a candidate gene expressed only in neuronal tissues. Using BAC clones, we determined the cDNA sequence and the gene structure of the candidate neuronal kinesin. Evolutionary analysis indicated that the candidate gene encoded medaka KIF5Aa. The endogenous medaka orthologue was found to be expressed only in the nervous system, including the brain and spinal cord, while expression of KIF5Ab was not exclusive to neuronal tissues. Transgenic (Tg) medaka that expressed EGFP under the control of the 6.9kbp 5' and 1.9kbp 3' flanking regions of the KIF5Aa gene showed characteristic expression throughout the nervous system, including the brain, spinal cord, olfactory pit, eye and cranial nerve. Immunohistological analysis showed that EGFP expression in Tg fish co-localized with expression of HuC/D, a neuronal marker. These results demonstrate that the 6.9kbp 5' and 1.9kbp 3' flanking regions of medaka KIF5Aa have neuronal-specific promoter activity mimicking endogenous expression of medaka KIF5Ab. This transgenic fish strain will be useful for further functional analysis of the effects of these regulatory regions on gene expression.
    Brain research 09/2012; 1480:12-21. DOI:10.1016/j.brainres.2012.08.047 · 2.84 Impact Factor
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