The Role of Kinesin Family Proteins in
Tumorigenesis and Progression
Potential Biomarkers and Molecular Targets for Cancer Therapy
Yue Yu, MSc1and Yu-Mei Feng, PhD1,2
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 com-
plex 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;116:5150–60. V
C 2010 American Cancer Society.
KEYWORDS: kinesin, mitosis, tumorigenesis, biomarker, molecular-targeted therapy.
The kinesin was discovered first in 1985.1To date, a total of 45 murine and human kinesin superfamily proteins (KIFs)
have been identified and classified into 14 families (termed kinesin-1 to kinesin-14) according to standardized nomencla-
ture for kinesins.2,3KIFs are a conserved class of microtubule-dependent molecular motor proteins that have adenosine
triphosphatase (ATPase) activity and motion characteristics.4The active movement of kinesins supports several cellular
functions, such as mitosis, meiosis, and the transport of macromolecules (eg, axonal transport).5In mitosis of eukaryotic
cells,kinesinsparticipateinspindleformation,chromosomecongressionand alignment,and cytokinesis.6Thereisindica-
tion that the abnormal expression and function of kinesins plays a key role in the development or progression of many
kinds of human cancers. Better understanding of kinesin protein functions may translate into the development of molecu-
lar-targeted therapy for various human cancers.7In addition,the evaluationof kinesin expression may identify biomarkers
forthe earlydetectionofhuman cancerand abetterindicationofprognosisforcancer patients.
Through analogic analysis of the protein structures of Kinesin-1, it is believed that kinesins form a heterodimer with
4 functional domains referred to as the 1) motor, 2) neck, 3) stalk, and 4) tail. The motor domain is connected through a
The ‘‘head’’ or motor domain consists of up to 360 amino acids with an ATP-binding site and an adjacent microtubule-
binding site. The function of the motor domain is to hydrolyze ATP to generate the energy needed for movement of the
proteins along microtubule fibers. The neck domain is often subtype-specific. In different kinesins, this subtype-specific
neck domain is essential for motility direction of the protein. The stalk domain is important for the interaction with other
subunits of the holoenzyme and intertwines to form the kinesin dimer. The tail domain is localized at the opposite end of
the protein and functions to interact with the transportation of cargo molecules, including proteins, lipids, or nucleic
acids.8-10The 14 families of kinesins can be grouped into N-kinesins, M-kinesins, and C-kinesins, which contain their
DOI: 10.1002/cncr.25461, Received: February 3, 2010; Revised: April 19, 2010; Accepted: May 4, 2010, Published online July 26, 2010 in Wiley Online Library
Corresponding author: Yu-Mei Feng, PhD, Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital,
Huanhuxi Road, Hexi District, Tianjin 300060, China; Fax: (011) 86-22-23537796; email@example.com
1Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China;2Key Laboratory of Breast Cancer Pre-
vention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
November 15, 2010
motor domain at the amino terminus, in the middle, or
at the carboxyl terminus, respectively. N-kinesins drive
microtubule plus end-directed transport, C-kinesins drive
minus end-directed transport, and M-kinesins depoly-
merize microtubules.11Among the KIFs, the motor
domain is highly conserved, whereas the ‘‘stalk/tail’’
region is highly divergent (Fig. 1). This reflects the diverse
cellular functions of kinesins, which range from synaptic
vesicle transportation, to the axon of neurons, to chromo-
In general, kinesins act as molecular motors to
transport cargo along microtubules in eukaryotic cells. In
addition, kinesins provide power for a variety of transpor-
tation needs during cell cycle progression, including
mitosis and meiosis. Kinesins also serve roles in ciliary and
flagellar genesis, microtubule polymer dynamics, and
signal transduction.12However, different subtypes of the
kinesin protein family may participate in different func-
tions in cells. For example, kinesin-1, kinesin-12, kinesin-
3, kinesin-4, kinesin-12, and kinesin-14 reportedly trans-
port organelles; whereas kinisen-1, kinesin-4, kinesin-5,
kinesin-6, kinesin-7, kinesin-8, kinesin-10, kinesin-12,
and kinesin-13 mainly participate in cell mitosis, particu-
larly in spindle formation, chromosomal and nuclear
movement, and cytokinesis. It has been demonstrated
that kinesin-11 participates in signal transduction. How-
ever,theprecise functionofkinesin-9 remainsunclear.4
To date, many studies have demonstrated that
altered expression of kinesins is associated with the devel-
opment and progression of various human cancers.13-23
Abnormal kinesin expression alters the equal distribution
of genetic materials during cell mitosis because of
chromosome hypercondensation, aberrant spindle forma-
tion, anaphase bridges, defective cytokinesis, aneuploidy,
Figure 1. The structure and functional domains of kinesin family proteins (KIFs) are illustrated. In general, kinesins comprise a
kinesin motor domain and a coiled-coil domain. There also are specific domains or regions, such as the pleckstrin homology (PH)
domain of KIF1B, the DNA binding domain of kinesin-like DNA binding protein (Kid), and nuclear localization signals (NLSs) of
KIF4A, mitotic kinesin-like protein 1 (MKLP1), Kid, and mitotic centromere-associated kinesin (MCAK). KHC indicates kinesin
heavy chain; Eg5, a kinesin spindle protein (KSP); CENP-E, centrosome-associated protein E; ATP, adenosine triphosphate.
Kinesin in Human Cancer/Yu and Feng
November 15, 2010
and mitotic arrest. The loss or gain of genetic materialwill
lead to numerous defects in the daughter cells and may
result in carcinogenesis with an aggressive behavior of
corresponding tumor cells. Therefore, the detection of
abnormal kinesin protein or messenger RNA (mRNA)
expression could be used as a biomarker for early tumor
diagnosis or to predict the survival of patients with cancer.
Moreover, because human cancer is a gene-related disease
with abnormalcell growth,targeting kinesins may create a
novel strategy for the control of human cancers. Indeed,
several such drugs are being studied successfully in clinical
trials. In this review, we discuss in detail the role of KIFs
in tumorigenesis and progression as well as their clinical
value as biomarkers and molecular targets for cancer
therapy. Important aspects of KIFs in relation to cancer
manifestation, progression, and therapy are summarized
Kinesin-1 was referred to previously as conventional kine-
sin: kinesin heavy chain (KHC). These proteins are capa-
ble of using chemical energy from ATP hydrolysis to
generate mechanical force. In the presence of ATP, kine-
sin-1 binds to and moves microtubules. The ability to
translocate along the microtubule lattice has led to the
classification of kinesin-1 as a microtubule motor protein.
However, the mechanism by which molecular motor pro-
teinsconvert energyfrom ATPhydrolysisintomechanical
force remains unclear. Kinesin-1 is abundant in virtually
all cell types at all stages of development and appears to be
free in the cytoplasm. However, some kinesin-1 is associ-
ated with various membrane-bound organelles, including
small vesicles and endoplasmic reticulum and membranes
that lie between the endoplasmic reticulum and Golgi
body. One of its members, KIF5B, participates mainly
in lysosome membrane and mitochondria transporta-
tion.24,25Hakimi et al26demonstrated that KIF5B func-
tions as a catalytic subunit of both nuclear factor 1 (NF-1)
(neurofibromin) and NF-2 (merlin) complex. Mutations
in either of these NF genes result in the development of
neurofibromatosis, a condition that predisposes individu-
als to develop a variety of benign and malignant tumors of
the central and peripheral nervous systems. This indicates
that KIF5B may be associated with neurofibromatosis.
Furthermore, it is reported that KIF5B mRNA was up-
regulated in several types of cancer tissues, including
cancers of the bladder, stomach, skin, and breast.27-30In
addition, Cardoso et al22observed that KIF5B protein
was highlyexpressedin various cancer cells, and the deple-
tion of KIF5B in HeLa cells induced lysosomal leakage
and cell death. The results from those studies suggest that
inhibition of KIF5B expression may be a promising target
It is believed that kinesin-2 drives membrane-associated
movements in axons, axonemes, and melanophores and
contains several proteins, such as KIF3A and KIF3B.
These proteins form a complex with other proteins to
exert their biologic function in the cells. For example,
Mans et al31reported that ATP-dependent motor com-
plexkinesin-2endogenously boundthe full-length variant
ofvon Hippel-Lindau tumor
(pVHL30)in primary kidney cells and increased its stabil-
ity with microtubules. The pVHL participates in many
cellular processes, including oxygen sensing, microtubule
stability, and primary cilia regulation. Inactivation of the
VHL gene by mutations/deletions caused sporadic renal
cell carcinoma and central nervous system hemangioblas-
toma.32Furthermore, Staller et al33demonstrated that
pVHL inhibited tumor metastasis through inactivation
of hypoxia-induced factor and inhibition of chemokine
(C-X-Cmotif) receptor4(CXCR4) geneexpression.
trimer with KIF3A/3B through its binding to the tail do-
main of the KIF3A/3B heterodimer34and links KIF3A/
3B with various cargo proteins, such as adenomatous
polyposis coli (APC)35and breast tumor kinase (BRK).13
Mutations in the APC gene affect the cell cycle and
promote tumor cell growth but suppress differentiation
and apoptosis, possibly because the mutant APC protein
derived from cancer cells is unable to accumulate effi-
ciently in clusters that are necessary for the interaction of
APC with KAP3-KIF3A-KIF3B to form a functional
complex.36-38In addition, conditional inactivation of the
KAP3 subunit of the KIF3 complex in neural progenitor
cells resulted in embryonic brain tumors.39Lukong and
Richard13demonstrated that KAP3 knockdown resulted
in the suppression of BRK-induced migration of breast
cancer cells and that the C-terminal deletion mutant of
KAP3 acted as a dominant negative in BRK-induced cell
migration. However, another study by Jimbo et al38indi-
kidney cells increased cell migration. These conflicting
data indicate that functions of the KAP3-KIF3A-KIF3B
complex may depend on cell type. Further investigations
will be necessary to elucidate the role of KAP3-KIF3A-
November 15, 2010
Table 1. Kinesin Protein Families and Their Association With Tumorigenesis and Progression
Reported Function (References)
Relation With Tumor
Lysosome membrane and mitochondria
transportation (Nakata & Hirokawa 1995,24Tanaka
Up-regulated in several types of cancer
tissues (Cardoso 2009,22Dyrskjot 2004,27
Hippo 2002,28Nindl 2006,29Richardson
A promising target for
Organelle, intraflagellar transportation and
spermatogenesis (Miki 20054)
Tumorigenesis and metastasis of breast
cancer, renal cell carcinoma (Lukong &
Richard 2008,13Jimbo 200238)
Mitochondria and synaptic vesicle transportation
(Nangaku 1994,40Matsushita 200441)
Metastasis of nervous system tumors and breast
cancer (Li 2009,14Bagchi 200742)
mRNA is a marker for
predicting prognosis inbreast cancer (Li 200914)
Cytokinesis (Carleton 2006,45Gruneberg 200646)
Tumorigenesis of primary breast, lung and
retinoblastoma tumors (Corson 2006,15
A prognostic indicator of
outcome in breast and lung
cancer (Corson 2006,15
Mitosis, including chromosome condensation (Zhu
Tumorigenesis of cervical cancer and
nonsmall cell lung cancer (Taniwaki 2007,18
A promising target for
A major inhibitor of the mammalian Hedghog
pathway (Cheung 200951)
Tumorigenesis and metastasis of many tumors
(Feng 2005,52Tremblay 2009,53Sarangi
Essential for cell proliferation; plays an important
role in mitosis (Castillo 2007,20Le Guellec 199155)
High expression in many tumors and related to
tumorigenesis (Castillo 2007,20
Le Guellec 199155)
A potent target for cancer
Cytokinesis (Chen 200559)
Deletion can inhibit cytokinesis of tumor cells
Potential target for cancer
Spindle assembly of mitosis (Cesario 200660)
Overexpressed in pancreatic ductal
adenocarcinoma cells (Taniuchi 200564)
Potential target for cancer
Aligns chromosomes and modulates the spindle
checkpoint (Wood 1997,65Kapoor 2006,66Schaar
1997,67Yao 2000,68Mao 200369)
Inhibition of CENP-E can inhibit growth in many
tumor types (Weaver 2003,70
McEwen 2001,71Chua 2007,72Sutton
Inhibitions of CENP-E
currently are undergoingclinical trials
Chromosome congression and alignment (Stumpff
The homologous gene SW108 is expressed at
the mRNA level in the majority of tumor cells
A potential target for cancer
Chromosome arm orientation, chromosome
oscillation and congression (Levesque & Compton
Overexpressed in proliferating breast cancer but
down-regulated in invasive and
metastatic tissue (Feng 200616)
mRNA expression has been
shown to be a biomarker
of diagnosis and
prognostic indicator of
outcome in breast cancer
Kinetochore-microtubule attachment (Ishikawa
Tumorigenesis and metastasis of many
tumors(Nakamura 2007,88Ishikawa 2008,89
Shimo 2008,90Scanlan 200291)
A potential target for cancer
therapy and for predicting
lymph node metastasis
Spindle assembly (Cai 200992)
Essential for extra centrosome-containing cancer
cells (Kwon 200893)
A potential target for cancer
HsuKHC/KIF5B indicates human motor protein kinesin-1 heavy chain/kinesin family protein 5B; KIF, kinesin family protein; Eg5, a kinesin spindle protein; mRNA, messenger RNA; MKLP1, mitotic kinesin-like protein 1; CENP-E, centro-
some-associated protein E; MACK, mitotic centromere-associated kinesin.
Kinesin-3 family proteins function as organelle transport-
ers. KIF1B, a kinesin-3 member, participates mainly in
vesicles.40,41KIF1B expression is lost in many different
tumor cells, indicating that KIF1B insufficiency may lead
to tumorigenesis in normal cells, especially when com-
bined with the loss of other contiguous 1p genes like the
chromodomain helicase DNA binding protein 5 (CHD5)
gene.42,43Schlisio et al19demonstrated that KIF1Bb is
necessary for inducing neuronal apoptosis and that
decreased KIF1Bb levels can protect the neural cells
against apoptosis and, in turn, cause neuroblastoma and
pheochromocytoma. However, complete loss of KIF1Bb
promotes neuronal apoptosis.44These conflicting data
indicate that the KIF1B gene plays different roles in
tumorigenesis and progression. Indeed, our previous
study indicated that the 5-year disease-free survival and
metastasis-free survival rates among patients with breast
cancer who had low levels of KIF1B mRNA were poorer
than the rates among patients who had high levels of
KIF1B mRNA.14We demonstrated that the detection
of KIF1B mRNA is an independent molecular marker for
(siRNA)-based gene knockdown studies have verified the
role of KIF14, another kinesin-3 member, in the cyto-
kinesis of eukaryotic cells.45,46KIF14 is a microtubule
motor that is amplified and overexpressed in breast can-
cer, lung cancer, and retinoblastoma.15,47It has been
demonstrated that altered KIF14 mRNA expression is a
prognostic indicator for patients with breast cancer and
lung cancer.15,17The absence of KIF14 in HeLa cells
reportedly resulted in a failure to complete cytokinesis,
producing binucleated cells that underwent apoptosis
after failed mitosis.45Functionally, KIF14 protein is
localized at the spindle midzone (the area formed between
retreating chromosomes as they segregate toward the
spindle poles in anaphase) and the midbody (the cyto-
plasmic bridge that connects 2 daughter cells at the end of
cytokinesis in telophase).45,46Therefore, targeting KIF14
may beanovelstrategyforcancer therapy.
Among kinesin proteins, KIF4A plays important roles in
the regulation of eukaryotic cell mitosis by participating
in chromosome condensation and segregation, spindle
segregation, and cytokinesis during cell mitosis.6,48Alter-
ation of KIF4A expression has been observed in different
human cancers. For example, Narayan et al49reported
that the expression of KIF4A mRNA in cervical cancer
was much higher than that in normal tissues. Taniwaki
et al18demonstrated that the KIF4A gene was activated in
nonsmall cell lung cancer (NSCLC) cells and that treat-
ment of NSCLC cells with specific siRNA to knockdown
KIF4A expression resulted in the suppression of cancer
cell growth. Moreover, patients with NSCLC who had
KIF4A-positive tumors had a shorter cancer-free survival
than patients who had KIF4A-negative tumors. In addi-
tion, KIF4A was classified as 1 of the typical cancer testis
antigens. The selective inhibition of KIF4A activity by
molecular-targeted agents was a promising therapeutic
strategy that was expected to have powerful biologic anti-
tumor activity with minimal adverse events. However,
some conflicting results have been reported recently. For
example, Mazumdar et al50performed in vivo and in vitro
experiments to demonstrate that loss of KIF4A leads to
multiple mitotic defects, including chromosome mis-
alignments, spindle defects, and aberrant cytokinesis,
which may cause tumorigenesis. Further studies will be
required to gain a better understanding of the role of
KIF4Aincancer development andprogression.
In addition, KIF7, another member of the family, is
a potent inhibitor of the mammalian Hedgehog (Hh)
pathway.51The latter is activated in many kinds of tumor
cells, and recent evidence suggests that blocking aberrant
Hh pathway signaling may be a promising therapeutic
strategy for the treatment of several types of cancers.52-54
These data suggest that the induction of KIF7 expression
or activity may control human cancers effectively and,
thus,may beused as atherapeutic tool.
Kinesin spindle proteins (KSPs), such as KIF11/Eg5,
belong to the kinesin-5 family and play an important role
gation. Thus, KSPs are essential for cell growth and
survival. In nonproliferating cells and tissues in adults, the
expression of KSP remains undetectable, whereas its
expression is prominent in proliferating cells and tissues
during development.20,55Increased expression of Eg5
reportedly is associated with tumorigenesis. For example,
Castillo et al20demonstrated that transgenic mice that
overexpressed Eg5 were prone to the development of a
variety of tumors. Dimethylenastron, an Eg5 inhibitor,
effectively inhibited tumor cell proliferation and induced
apoptosis of pancreatic cancer cells and in nude mouse
xenografts.56To date, several inhibitors of Eg5 (eg,
November 15, 2010
monastrol and ispinesib) have been used successfully in
the clinic. Liu et al57observed that the suppression of Eg5
by monastrol arrested mitosis and induced apoptosis but
up-regulated heat-shock protein 70 (Hsp70) in human
multiple myeloma cells. The up-regulation of Hsp70
enhanced antiapoptosis in cells as an unexpected side
effect. This finding indicates that a combination of Eg5
inhibitors with agents that abrogate Hsp70 induction
may be useful as therapy for myeloma. Saijo et al58
reported that the response rate of patients with Eg5-posi-
tive NSCLC to chemotherapy was 37% compared with
10% in patients with Eg5-negative NSCLC, suggesting
that the detection of Eg5 expression may be a useful
biomarker for predicting the response to antimitotic
agents plus platinum chemotherapy in patients with
A kinesin-6 member, mitotic kinesin-like protein 1
(MKLP1) (also known as KIF23) is essential for cyto-
kinesis. Chen et al59observed that reduced MKLP1
expression led to severe inhibition of proper midbody
sis, thus, resulting in the death (apoptosis) of tumor cells
by using RNA interference (RNAi) to knockdown
MKLP1 expression. This finding indicates that targeting
MKLP1may beused todevelopcancertherapydrugs.
Furthermore, MKLP2/KIF20A, another member of
kinesin-6 family, also participates in spindle assembly
during mitosis.60By using microarray analysis, Wonsey
and Follettie61observed that forkhead box M1 (FoxM1)
up-regulated MKLP2, which was essential for faithful
mitosis, and the expression of FoxM1 was correlated with
the proliferative status of a variety of normal and trans-
formed cell types. Consistent with a role in proliferation,
elevated expression of FOXM1 has been reported in both
basal cell carcinoma of the skin and in hepatocellular
carcinoma.62,63In addition, Taniuchi et al64reported
that pancreatic ductal adenocarcinoma strongly over-
expressed MKLP2 protein, and knockdown of endoge-
nous MKLP2 levels in pancreatic adenocarcinoma cell
lines using siRNA dramatically attenuated tumor cell
growth. These findings indicate that MKLP2 also may be
Centrosome-associated protein-E (CENP-E) (also known
as KIF10) is localized at kinetochores that have 2 func-
tions. Acting as a motor protein, CENP-E positions chro-
mosomes on the metaphase plate by sliding unattached
kinetochores toward the spindle equator along micro-
tubule bundles referred to as kinetochore fibers (K-
fibers).65-67In addition, CENP-E modulates the spindle
checkpoint by directly binding to the mitotic checkpoint
Bub1-related protein BubR1 and stimulating its kinase
activity, representing a link between the attachment of
spindle microtubules and the mitotic checkpoint-signal-
ing cascade.68,69Loss of CENP-E expression or altered
function of CENP-E leads to inhibition of chromosome
alignment during mitosis, resulting in the initiation of
checkpoint activation and a delay in the completion of
cell mitosis.70,71The inhibition of CENP-E using a
potent and selective CENP-E inhibitor GSK923295A
reportedly delayed the duration of cell mitosis, as charac-
terized by the presence of lagging, nonequatorially aligned
chromosomes associated with the spindle pole, and this
was followed by apoptosis.72,73Several investigators have
reported the efficacy of GSK923295A in nude mouse
xenografts,74and its antitumor effects are the subject of
current phase 1 clinical trials in patients with advanced
solid tumors. In addition, CENP-E is regulated function-
ally by farnesylation; thus, the suppression of CENP-E
farnesylation using a farnesyl transferase inhibitor, lona-
farnib, also may have antitumor effects. Indeed, such an
inhibitor is being evaluated currently in multiple clinical
trials for the treatment of solid tumors.75,76However,
once CENP-E expression is altered in cells, the chromo-
somes cannot separate normally, and this may result in
aneuploidy, which is a hallmark in most solid cancers,
such as hepatocellular carcinoma (HCC).77Liu et al78
observed that CENP-E expression was reduced in HCC
tissue, and low CENP-E expression resulted in aneu-
ploidy in the normal liver cell line LO2. However, those
authors did not provide direct evidence that reduced
expression of CENP-E can initiate hepatocarcinogenesis.
Further studies are needed to gain a better understanding
ofthe roleof CENP-Ein tumorigenesis.
It has been demonstrated that kinesin-8 family member
KIF18A plays key roles in the regulation of chromosome
congression during prometaphase and in the maintenance
of chromosome alignment during metaphase.79The use
of RNAi to knockdown KIF18A expression resulted in
aberrantly elongated spindle microtubules, loss of tension
across sister kinetochores, activation of the spindle
checkpoint, and mitotic arrest.4,80Shichijo et al23studied
a tumor-associated antigen recognized by cytotoxic
Kinesin in Human Cancer/Yu and Feng
November 15, 2010
T lymphocytes that has high homology with KIF18A.
They observed that this unique gene was expressed at high
levels in the majority of cancer cells but not in many nor-
mal tissues, with the exception of testis and lung. In addi-
tion, Zusev and Benayahu81reported that both estrogen
and estrogen receptor (ER)-a could up-regulate the expres-
sion of KIF18A mRNA and protein in vivo and in vitro.
This finding indicates that KIF18A may be associated with
ER-related cancers. Together, these results indicate that
The kinesin-like DNA binding protein (Kid)/kinesin-like
4 (KNSL4)/KIF22 belongs to the kinesin-10 family, and
studies have demonstrated that it is involved in chromo-
some arm orientation, chromosome oscillation, and
congression on the metaphase plate of the mitotic spin-
dle.82,83Kid, as a DNA binding protein, functions as a
transcription factor (trans-acting factor) by binding to the
corresponding regulatory DNA sequence (cis-acting
element) of the target genes.84In addition to the DNA-
binding domain, Kid also contains 2 conventional basic
nuclear localization signals (NLSs).85Therefore, it local-
izes to the nucleus in normal cells. However, Bruzzoni-
Giovanelli et al86reported that Kid expression was more
diffuse (cytoplasmic) in tumor cells. Their report
indicated that NSLs may mutate in tumor cells. In our
previous study, we observed that KNSL4 mRNA and its
coded protein, Kid, were not detectable in normal tissues
but were overexpressed in proliferating breast cancer tis-
sues, whereas they were down-regulated in invasive and
metastatic breast cancer cells. In addition, patients who
had breast cancer with low KNSL4 mRNA expression had
much a poorer disease-free survival rate than patients with
higher expression (unpublished data). Therefore, the
detection of KNSL4 mRNA expression may be evaluated
furtheras abiomarkerin breastcancer.
The kinesin-13 family, namely, the mitotic centromere-
associated kinesin (MCAK)/kinesin-like 6 (KNSL6)/
KIF2C protein, is essential for kinetochore-microtubule
attachment during spindle formation in cell mitosis and
possesses microtubule depolymerizing activity.87A study
of its association with human cancer revealed that MCAK
was highly expressed in colorectal and gastric cancer
tissues compared with its expression in corresponding
normal tissues. This elevated expression was associated
with lymph node metastasis, venous invasion, and perito-
neal dissemination of colorectal cancer cells.88,89Again,
The expression of MCAK mRNA in patients with colo-
rectal cancer was related to a much poorer survival rate
than that in patients who had low levels of MCAK mRNA
expression.89Furthermore, the suppression of MCAK
These findings suggest that targeting the MCAK gene may
effectively control human cancers and that the detection
of MCAK expression could be used as a tumor biomarker
for early diagnosis or prognosis. Indeed, a recent study
demonstrated that MCAK protein was detected in the pe-
ripheral blood stream of patients with colon cancer,91and
this finding should be evaluated further to determine
whether the detection of MCAK in blood can be used for
earlydiagnosisor forpredicting tumormetastasis.
The Kinesin-14 proteins (formerly known as the C-termi-
nal motor proteins) have in common a C-terminal motor
domain, differing from other kinesin proteins. It has been
observed that at least 4 members of the group (Drosophila
melanogaster nonclaret disjunctional protein [DmNcd],
Saccharomyces cervisae kinesin-like protein [ScKAR3],
Cricetulus griseus Chinese hamster ovary protein 2
calmodulin binding protein [AtKCBP]) are minus end-
directed motors, in contrast to the plus end-directed
motility of other kinesin proteins. These minus end-
directed motors of kinesin-14 family proteins that cross-
link microtubules play key roles during spindle assembly.
KIFC1, a normally nonessential kinesin motor, promotes
the outward movement of the spindle poles and increases
the half-spindle length of the monopolar spindle. It is
essential for the viability of certain extra centrosome-con-
taining cancer cells.92,93Knockdown of human KIFC1
gene expression with siRNA induced a dramatic increase
in multipolar anaphases, in which nearly 100% of cells
contained extra centrosomes, but had no effect on cell
division and viability in control cells, raising the prospects
of a tumor-selective kinesin drug target.93In addition,
resistance to chemotherapy remains a major barrier to the
successful treatment of cancer. De et al94demonstrated
that breast cancer cells with overexpressed KIFC1 became
more resistant to docetaxel. This finding may lead to
novel therapeutic approaches in which KIFC1 inhibitors
Summary and Future Directions
It has not been long since the first kinesin was discovered,
and 14 kinesin family members, each containing various
November 15, 2010
proteins, have been identified. These microtubule-based
molecular motors play an essential role in eukaryotic cell
mitosis and macromolecule transportation. Alteration of
their expression and functions leads to human disease,
ple, alterations of KIF3,13KIF1B,14KIF14,15and Kid16
proteins were observed in breast cancer; KIF1417and
KIF4A18were altered in lung cancer; and KIF1B was
down-regulated in neurofibroma.19In addition, altered
KIF18A23proteins was associated with the development
of different human cancers. Thus, an analysis of their
expression may serve as useful tools for the early detection
of tumorigenesis and for better predictions of prognosis
for patients with cancer. Targeting these proteins in
human cancer cells will be a novel antitumor strategy in
the effectivecontrolofhuman cancers.
Although the functions of kinesin proteins include
mitosis and transportation of macromolecules in the cells,
and alteration of their expression leads to carcinogenesis
and cancer progression, the underlying molecular mecha-
nismsresponsiblefortumordevelopment and progression
remain to be elucidated. Summarizing from previous
studies, the expression of KIFs is regulated by the
upstream transcription factor. For example, KIF1Bb is
regulated by egl9 homolog 3 (EglN3),19MKLP1 is
regulated by cut-like homeobox 1 (CUX1) and E2F tran-
scription factor 1 (E2F1),95MKLP2 is regulated by fork-
head box M1 (FoxM1),61and MCAK is regulated by Sp
transcription factor 1 (Sp1) and E2F1.96The phosphoryl-
ation of KIFs reduced their binding to microtubules97,98
and changed the localization and microtubule depoly-
merizing activity of KIF.99After executing their functions
(such as regulation of the cell cycle), KIFs are degraded
through the ubiquitin proteasome pathway at the
anaphase of cell cycles (such as Kid100and KIF18A101).
However,thisis nottrueforEg5,whichis repressedtrans-
criptionally by Parkin, an E3 ubiquitin ligase, through
blocking c-Jun binding to the AP1 site of the Eg5 gene
promoter.102Taking these findings together, in future
studies, the molecular mechanisms responsible for the
dysfunctions and alterations of these transporters warrant
further investigation. For example, the cause of aberrant
KIF expression and the translocation of KIFs in cells for
altered gene signaling need to be investigated. Meanwhile,
it is urgently important to determine the causes of abnor-
mal mitosis in cells, which may lead to a better under-
standing of fundamental cell biology. Further studies also
will clarify how these genes participate to change cell
behaviors, such as migration and proliferation, and
whether these genes have the ability to compensate each
other’s functions in the cells. Answers to these questions
will provide crucial clues for clarifying the cellular func-
tions and roles of kinesin proteins, helping us to develop
novel strategies for better early detection and treatment of
CONFLICT OF INTEREST DISCLOSURES
Supported by grants from The National Natural Science Foun-
dation of China (no. 30471671 and no. 30872518), the Applied
Basic Research Program of Tianjin (no. 06YFJMJC12900),
the Major Program of Applied Basic Research Projects of
Tianjin (no. 09JCZDJC19800), and the Program for Chang-
jiang Scholars and Innovative Research Team in University by
the Ministry of Education (no. URT0743).
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