(The FASEB Journal. 1999;13:773-780.)
© 1999 FASEB
Cyclin E in human cancers
RORY DONNELLAN1 and
RUNJAN CHETTY
Department of Pathology, University of Natal Medical School, Durban, South Africa
1Correspondence: Department of Pathology, University of Natal Medical School, Private Bag 7, Congella 4013, Durban, Kwazulu-Natal, South Africa. E-mail: donnellanr{at}med.und.ac.za
 |
ABSTRACT
|
|---|
Regulators of the cell cycle such as cyclin E play an important part in
neoplasia. The cyclin E protein forms a partnership with a specific
protein kinase. This complex phosphorylates key substrates to initiate
DNA synthesis. Cyclin-dependent kinase inhibitors (CKIs) are able to
suppress the activity of cyclin E. Various substances (including
proteins produced by oncogenic viruses) affect cyclin E directly or
indirectly through an interaction with CKIs. These interactions are
important in elucidating the mechanisms of neoplasia. They may also
provide prognostic information in a wide range of common cancers.
Cyclin E may even be a target for treatment of cancers in the
future.—Donnellan, R., Chetty, R. Cyclin E in human cancers.
Key Words: cell cycle • cyclins • cyclin-dependent kinase • CKIs
|
INTRODUCTION
|
|---|
NEOPLASIA IS CHARACTERIZED by abnormal regulation of
the cell cycle. Although p53 is still the most important cell cycle
regulator in human neoplasms, there is growing recognition of the role
of the cyclins. The cyclins are an ever-growing group of proteins that
form the regulatory subunits in complexes with a specific catalytic
protein kinase (cyclin-dependent kinase) partner. The cyclins bind to
cyclin-dependent kinases (cdks)2
using a
conserved 87 amino acid sequence, termed the cyclin box. At present, 10
classes of cyclins (designated A–J) are known; within some classes a
number of subclasses (e.g., cyclins D1, D2, and D3) exist, so that in
total there are 15 different mammalian cyclins. Recently, there has
been a focus on cyclin D1 (1)
. This review aims to draw attention to
another important G1 phase regulator, cyclin E, which is a 395 amino
acid protein (2)
derived from a gene on chromosome 19q12–>q13 (3)
.
Cyclin E contributes to normal cell proliferation and development (4,
5), but its aberrant expression in neoplasia has become the subject of
particular interest after the realization that overexpression of cyclin
E can accelerate the G1 phase of the cell cycle (6)
.
|
CYCLIN E AND pRB
|
|---|
Both cyclin D1 and E drive cell proliferation forward by
phosphorylating the product of the retinoblastoma gene (pRB).
Hyperphosphorylated pRB then releases bound transcription factors of
the E2F family to cause DNA synthesis. Cyclin E is both a regulator and
a target of the E2F transcription family in an autoregulatory loop that
is necessary for progression from the G1 to the S phase of the cell
cycle (7
8
9)
(Fig. 1
). Under normal circumstances, pRB phosphorylation requires cyclin
D/cdk4 prior to the action of cyclin E/cdk2 (11,
12)
. However, some
malignant cells may preferentially use only one cyclin to accomplish
the task of phosphorylating pRB, making the other cyclin redundant
(13
14
15
16)
. In a study using myeloblastic leukemia cell lines, cyclin E
appeared more important in cell proliferation whereas cyclin D1 was
involved in cell differentiation (17)
. The same may apply to other
tumors, such as breast carcinomas (18,
19)
, but more research is needed
to confirm these findings.
View larger version (26K):
[in this window]
[in a new window]
|
Figure 1. The cell cycle is divided into four phases: the S phase (during which
DNA synthesis occurs) and the M (mitotic) phase are separated by two
resting phases: the G1 and the G2 phases. Different combinations of
cyclin complexed with cyclin-dependent kinase (cdk) regulate various
phases of the cell cycle. Cyclin E joins with cdk2 to regulate the
transition from the G1 to the S phase. During the cycle, several
checkpoints exist that ensure structural integrity of the genome prior
to replication and division. The most notable checkpoint is regulated
by p53 in mid-to-late G1 phase (modified from ref 10
).
|
|
|
CKIs
|
|---|
Whether cyclin E (or D1) phosphorylates pRB is dependent on levels
of a recently discovered group of molecules, termed the
cyclin-dependent kinase inhibitors (CKIs) (20)
. As their name suggests,
the CKIs are able to bind to and inhibit active cyclin/cdk complexes.
CKIs can be divided into two groups based on structure and function:
the Kip/Cip proteins (consisting of p21, p27, and p57) and the INK4
proteins (p15, p16, p18, p19). Whereas the INK4 proteins are relatively
specific inhibitors of complexes containing the D-type cyclins, the
Kip/Cip family can inhibit a wide variety of cyclins. Although all of
the Kip/Cip family have been shown to be capable of inhibiting cyclin E
(21
22
23)
, p21/Cip1 and p27 have attracted the most attention. p21 is an
important intermediary molecule because it is under the transcriptional
control of p53. Accumulation of normal (wild-type) p53 is known to
arrest cells in G1. Its actions on p21 and, thence, cyclin E may
clarify the mechanisms involved in G1 phase arrest (Fig. 1)
. Increased
binding of p21 to cyclin E-Cdk2 is also the mechanism of action for the
growth suppression/inhibition of:
BRCA1, a gene important in familial breast and ovarian
cancers (24,
25)
;
transforming growth factor ß in head and neck squamous
carcinomas (26)
;
cross-linked cell surface anti-immunoglobulin M in human lymphoma
cell lines (27)
;
potent prostaglandin A1 analogs in glioma cell lines (28)
;
concanavalin A and phorbol 13-myristate 12-acetate in murine T
lymphoma cell lines (29)
.
The ability of p27 to inhibit growth in human cancers through
interaction with cyclin E-Cdk2 has also been amply demonstrated (23,
30
31
32
33)
. Some of the mechanisms of this interaction have been
elucidated (34)
. Ancillary pathways using p27, such as E-cadherin
induced contact inhibition (35)
, have now been discovered. Also of note
is the demonstrated ability of p27 to act not only as an inhibitor, but
also as a target of cyclin E/cdk2 (36)
(Fig. 1)
.
Although the mechanism of action of 
-interferon is thought to
operate via inhibitory effects on Cdks complexed with cyclin E (37,
38)
, it is not yet clear whether this involves any of the CKIs. The
observed effect of exogenous and endogenous growth factors such as
basic fibroblast growth factor (39)
, epidermal growth factor, and
cementum-derived growth factor (40)
to stimulate cyclin E is also
likely to operate via CKIs.
|
OTHER MECHANISMS OF S-PHASE INDUCTION
|
|---|
Recent evidence suggests that cyclin E may be able to promote the
S phase by using pathways that do not involve pRB (41
42
43
44)
. This was
most convincingly demonstrated by Leone et al. (45)
when they showed
that Myc and Ras coexpression led to cyclin E-dependent kinase activity
and S phase induction without pRB phosphorylation. The mechanism of
action of Myc and Ras is mainly indirect, by disinhibition rather than
direct activation of cyclin E, since Myc and Ras collaboration leads to
a dramatic decrease in the levels of p27, one of the CKI proteins known
to inhibit cyclin E/cdk2 complexes. Although how Myc, Ras, and
activated cyclin E complexes induce the S phase without phosphorylating
pRB was not fully explained, it was shown that Myc may bind directly to
promoter sequences activating E2F transcription factors. Subsequently,
however, Cyclin E/cdk2 complexes have been shown to phosphorylate and
thereby activate other transcriptional regulators important in cellular
proliferation such as human B-MYB (46)
and NPAT (47)
. It is likely that
we have only scratched the surface and that further interactions
between cyclin E and transcription factors will be discovered. However,
the scope for research is not restricted to transcription factors. The
association of cyclin E with pre-mRNA splicing machinery (48)
has
opened even more horizons.
|
CYCLIN E AND ONCOGENIC VIRUSES
|
|---|
There is growing support for a relationship between HPV and cyclin
E (49
50
51
52
53
54
55)
. HPV E7 protein (implicated in carcinogenesis, especially of
the uterine cervix) can interact with p21(Cip1) and abrogate
p21(Cip1)-mediated inhibition of cyclin A- and E-associated kinase
activities (56)
. This may be by blocking regions of the p21 molecule
important in the sequestration of cyclin E (57,
58)
. A similar role has
been suggested for cytomegalovirus (CMV), although in addition to
inactivation of CKIs, CMV also appears to induce cyclin E directly
(59)
. Herpesviruses, too, appear to be able to induce cell
proliferation by abrogating the effects of the CKIs (60)
. By contrast,
HIV-1 inhibits cyclin E activity by causing G1 phase arrest, which
supposedly fosters viral replication (61,
62)
.
|
CYCLIN E OVEREXPRESSION
|
|---|
Accumulation of cyclin E protein in most cases reflects
amplification of the gene (13,
63
64
65)
, although other mutations have
been detected. However, cyclin E is sometimes modified by
posttranscriptional mechanisms (66)
, so that increased protein
expression can occur without mutations in the cyclin E gene. Splice
variants that have structural or functional abnormalities in the cyclin
box have also been identified (67,
68)
. Immunolabeling localizes cyclin
E to the nucleus in the majority of neoplasms studied. However,
cytoplasmic staining is increasingly being observed, the significance
of which is unclear. Although the protein is synthesized and degraded
in the cytoplasm, it is ordinarily transferred rapidly to the nucleus
where it exerts its functions. Accumulation of cyclin E in the
cytoplasm may reflect increased synthesis, decreased degradation, or
failure of nuclear transfer. Because, in the latter scenario, cyclin E
can have little direct effect on cell division, the conventional wisdom
has been to regard as negative those tumors that show cytoplasmic
staining in the absence of any nuclear staining. As Albert Einstein
pointed out, "It is the theory that decided what can be observed."
Our own attempts to examine the factors that control transport of
cyclin E in and out of the nucleus have so far met with little success,
but clearly this area needs further investigation.
|
IS CYCLIN E A DRIVER GENE?
|
|---|
The question of whether cyclin E is merely a link in the
chain of events that lead to cell proliferation or whether it is a
driving force in cell replication is difficult to ascertain at present,
but appears to be tumor dependent. In some tumors, cyclin E gene
amplification and protein accumulation are late events (32,
64,
69,
70)
(supporting the former argument), whereas in other neoplasms an
increase in cyclin E is observed early in the progression to malignancy
(71,
72)
. Because extensive networking occurs between the various cell
cycle regulators, it is difficult to apportion sole responsibility on
any one of them. Thus, when examining the mechanisms in neoplasia, it
is often more meaningful to examine cyclin E together with other cell
cycle regulators. For instance, high levels of cyclin E may be
functionally inactivated by similarly large numbers of CKIs, such as
p21. This may be the explanation for the seemingly incongruous
association of high cyclin E levels with a good prognosis in cervical
adenocarcinoma (73)
.
|
BREAST CANCER
|
|---|
The morphological progression from normal and benign breast tissue
through ductal carcinoma in situ (DCIS) to invasive ductal
carcinoma is associated with accumulating levels of cyclin E (18)
.
Also, in high-grade DCIS there are significantly more cyclin E-positive
cells than in low-grade DCIS (72)
. In invasive breast cancers, cyclin E
has been found to be overexpressed out of proportion to other markers
of cell proliferation (74,
75)
, suggesting that dysregulated expression
of the gene may contribute to, rather than be a consequence of,
increased cell division. Increased expression of cyclin E has been
shown to correlate with poor grade (18)
and late-stage lesions (74)
as
well as negative estrogen receptor status (18,
76)
. However, whether
cyclin E expression is predictive of prognosis independent of standard
clinicopathological factors such as tumor size, lymph node, and distant
metastases, as well as estrogen receptor status, is not yet clear. It
has been shown that cyclin E is associated with a poor prognosis even
in node-negative patients (66,
76)
, although the strong correlation
with negative estrogen receptors may be a confounding variable in these
studies. Whether cyclin E alone or in combination with other proteins
(such as p27) (77)
allows better prognostic stratification than
standard clinicopathological parameters needs further study before
incorporation into the routine workup of breast cancer patients can be
advocated.
|
GASTROINTESTINAL MALIGNANCIES
|
|---|
Different cell cycle regulatory genes are implicated in carcinomas
at various sites along the gastrointestinal tract (78)
. Cyclin E
appears to be more important in stomach and colorectal cancers than in
cancers at other sites. The cyclin E gene is amplified in ~15% of
human gastric carcinomas, although even greater percentages show
increased mRNA and protein levels (64,
70,
79,
80)
. High levels of
cyclin E (in association with low p21 or p27 levels) correlate with
depth of tumor invasion and advanced stage in gastric carcinoma (32,
64,
69,
70,
80)
. Recently the combined variable of cyclin E with often
coexpressed p53 protein expression has been shown to be of independent
prognostic significance in gastric carcinoma (81)
. Thus, assessment of
cyclin E in preoperative biopsies may provide valuable information in
stratifying patients with gastric carcinoma for different treatment
protocols.
Cyclin E gene amplification is also apparent in ~10% of colorectal
carcinomas, in some instances together with cdk2 gene amplification
(63)
. At the protein level, colorectal cancers not only show higher
levels than adjacent nonneoplastic mucosa (82)
but there appears to be
a gradual accumulation of cyclin E protein in the morphological
progression from adenoma to adenocarcinoma (83)
. Cyclin E protein
levels also correlate with grade of atypia in adenomas, stage of
carcinoma, and p53 and Ki-67 levels (83)
.
|
HEMATOLOGICAL MALIGNANCIES
|
|---|
In one study on adult human lymphoblastic leukemia (ALL), it was
found that cyclin E protein expression was significantly increased in
relapsed samples compared with pretreatment results (84)
. However, in
another similar study, cyclin E protein expression was not associated
with any difference in the duration of relapse-free intervals or the
frequency of recurrence in childhood ALL patients (85)
. Promyelocytic
leukemia (PML) is an important growth-suppressing protein, disruption
of which by t(15;17) in acute promyelocytic leukemia plays a critical
role in leukemogenesis (86)
. PML has been shown to suppress cell growth
by increasing cell cycle duration primarily by elongation of G1. One of
the ways PML functions is to reduce levels of cyclin E. In an initial
study on acute myeloid leukemia, the rates of complete remission and of
disease-free survival were low in patients with M4 or M5 leukemia
blasts with overexpressed cyclin E (87)
. Cyclin E overexpression is not
confined to acute leukemias. Chronic lymphocytic leukemia, and
Hodgkin's and non-Hodgkin's lymphomas, have also been associated with
high levels of cyclin E (33,
88)
, although the significance has not
been defined. In the 105 lymphomas that Erlanson et al. (33)
studied,
cyclin E was associated with poor prognosis. However, this association
was not apparent on multivariate analysis.
|
GENITO-URINARY TRACT CANCERS
|
|---|
Cyclin E appears to be an important early factor in cervical
squamous cell carcinomas (52,
55)
through its link with transforming
types of human papilloma viruses (as noted above). However, the
prognostic significance of cyclin E in squamous cell carcinomas is not
yet clear (89)
.
Cyclin E immunostaining is a feature of most endometrial carcinomas
(90)
. As has been demonstrated in breast cancers, an inverse
correlation between positive estrogen receptor status and cyclin E
immunostaining appears to exist in endometrial carcinomas, but not in
adjacent normal or hyperplastic epithelium from the same patients (91)
.
Although cyclin E is not restricted to neoplastic endometrial
disorders, since increased levels of cyclin E are noted during the
normal proliferative phase (92)
, there does appear to be an
accumulation of this protein from normal through simple and complex
hyperplasia to malignancy (91,
93)
. Although correlations with serous
type, grade, and stage have been suggested (91,
93)
, the prognostic
implications of cyclin E need to be studied in greater detail (90)
.
Between 12% (13)
and 21% (65)
of ovarian cancers show cyclin E
amplification, with a slightly higher percentage showing increased
protein expression. However, no correlation has been observed between
amplification of the cyclin E gene and tumor type, stage, or grade in
these tumors.
Cyclin E immunopositivity correlates (together with p53) with
high grade and poor prognosis in transitional cell carcinomas of the
renal pelvis and ureter (94)
. This is not the case in aggressive
bilharzial-related bladder cancers, where cyclin D1 appears to be a
better prognostic marker even though a high percentage of cases are
immunopositive for cyclin E (95)
.
|
LUNG CANCER
|
|---|
Normal lung alveolar epithelial cells react to oxidant stress
through transforming growth factor-mediated induction of p21 and
subsequent inhibition of cyclin E/cdk2 complexes, giving cells time to
repair any mutations before the S phase in much the same manner as p53
(96)
. On the other hand, neoplastic bronchial epithelial cells
generally have high levels of functional cyclin E/cdk2 complexes (97)
.
Furthermore, it has been shown that those neoplastic cells with greater
active cyclin E/cdk2 complexes are more radiosensitive (98)
.
|
SKIN CANCERS
|
|---|
Cyclin E has been detected in a number of premalignant skin
lesions, but not in a high percentage of squamous cell carcinomas or
basal cell carcinomas (71)
. Mouse models suggest that the mode of skin
carcinogenesis may affect the expression of cyclin E and other cyclins
(99)
.
|
SARCOMAS
|
|---|
Cyclin E has been detected in a variety of primary human sarcomas
as well as sarcoma cell lines (16,
39,
100)
. Almost 50% of high-grade
osteosarcomas show positive immunostaining for cyclin E protein. In
these tumors, there is an association between cyclin E and cell
proliferation as detected by Ki-67 (16)
. The ability of proliferating
osteoblasts to inhibit cell differentiation in adjacent cells involves
interaction with cyclin E and may prove useful in delineating the
pathways involved in osteosarcomagenesis (101)
. In addition, assessment
of cyclin E (along with other cell cycle proteins) may be of value in
refining treatment protocols in some sarcomas (100)
.
|
MISCELLANEOUS
|
|---|
Many cyclins, including cyclin E, are increased in astrocytoma
cell lines (102)
and some head and neck squamous carcinoma cell lines
(103)
, but whether this has any bearing on prognosis will have to be
studied in primary human tumors. So far there are very few tumors in
which cyclin E appears to play little or no role. The exceptions that
remain result more from a lack of research than a lack of involvement.
For instance, initial indications that thyroid neoplasms did not
involve cyclin E pathways (104)
are now being eroded (105)
.
|
CONCLUSION
|
|---|
Investigation of cyclin E has provided insights into a number of
different neoplasms as well as into the process of neoplasia. So far,
the main value of cyclin E is in refining prognosis and treatment of
patients with a variety of common cancers.
|
FUTURE DIRECTIONS
|
|---|
In the future, cyclin E may become a target for treatment. In this
regard, the demonstrated effect of cell surface anti-immunoglobulin M
to suppress cyclin E and result in cancer dormancy holds hope (27)
.
Until then, there are a host of avenues to explore before we can fully
appreciate the intricacies of normal and neoplastic cellular processes.
One recently opened avenue with intriguing potential is the discovery
of a new G1 cyclin that has close structural homology with cyclin E and
has thus been designated cyclin E2 (106
107
108)
. Other than the deluge of
recent publications, perhaps the clearest indication that this is a
vibrant field is that cyclin E research continues to provide as many
questions as answers. Are there other substrates that are modified by
cyclin E/cdk2 phosphorylation? How does this phosphorylation affect
movement of proteins between the cellular compartments? What is the
role of phosphorylation in targeting proteins for degradation (109)
? In
fact, some important questions remain unasked.
As Rudyard Kipling advised:
"I keep six honest serving-men
They taught me all I know;
Their names are What and Why and When
And How and Where and Who"
|
FOOTNOTES
|
|---|
2 Abbreviations: ALL, acute lymphoblastic leukemia; cdk,
cyclin-dependent kinase; CKIs, cyclin-dependent kinase inhibitors; CMV,
cytomegalovirus; DCIS, ductal carcinoma in situ;
PML, promyelocytic leukemia; pRB, retinoblastoma
protein. 
|
REFERENCES
|
|---|
-
Donnellan, R., Chetty, R. (1998) Cyclin D1 and human neoplasia. J. Clin. Pathol. 51,1-7[Medline]
-
Koff, A., Cross, F., Fisher, A., Schumacher, J., Leguellec, K., Philippe, M., Roberts, J. M. (1991) Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell 66,1217-1228[Medline]
-
Demetrick, D. J., Matsumoto, S., Hannon, G. J., Okamoto, K., Xiong, Y., Zhang, H., Beach, D. H. (1995) Chromosomal mapping of the genes for the human cell cycle proteins cyclin C (CCNC), cyclin E (CCNE), p21 (CDKN1) and KAP (CDKN3). Cytogenet. Cell. Genet. 69,190-192[Medline]
-
Sauer, K., Lehner, C. (1995) The role of cyclin E in the regulation of entry into the S phase (review). Prog. Cell Cycle Res. 1,125-139[Medline]
-
Keyomarsi, K., Herliczek, T. W. (1997) The role of cyclin E in cell proliferation, development and cancer (review). [164 refs]. Prog. Cell Cycle Res. 3,171-191[Medline]
-
Wimmel, A., Lucibello, F. C., Sewing, A., Adolph, S., Muller, R. (1994) Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E. Oncogene 9,995-997[Medline]
-
Ohtani, K., DeGregori, J., Nevins, J. R. (1995) Regulation of the cyclin E gene by transcription factor E2F1. Proc. Natl. Acad. Sci. U. S. A. 92,12146-12150[Abstract/Free Full Text]
-
Geng, Y., Eaton, E. N., Picon, M., Roberts, J. M., Lundberg, A. S., Gifford, A., Sardet, C., Weinberg, R. A. (1996) Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 12,1173-1180[Medline]
-
Pierce, A. M., Gimenez-Conti, I. B., Schneider-Broussard, R., Martinez, L. A., Conti, C. J., Johnson, D. G. (1998) Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53. Proc. Natl. Acad. Sci. U. S. A. 95,8858-8863[Abstract/Free Full Text]
-
Cordon-Cardo, C. (1995) Mutation of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J. Pathol. 147,545-560[Abstract]
-
Resnitzky, D., Reed, S. I. (1995) Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol. Cell. Biol. 15,3463-3469[Abstract]
-
Lundberg, A. S., Weinberg, R. A. (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol. Cell. Biol. 18,753-761[Abstract/Free Full Text]
-
Courjal, F., Louason, G., Speiser, P., Katsaros, D., Zeillinger, R., Theillet, C. (1996) 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. Int. J. Cancer 69,247-253[Medline]
-
Gray-Bablin, J., Zalvide, J., Fox, M. P., Knickerbocker, C. J., DeCaprio, J. A., Keyomarsi, K. (1996) Cyclin E, a redundant cyclin in breast cancer. Proc. Natl. Acad. Sci. U. S. A. 93,15215-15220[Abstract/Free Full Text]
-
Nielsen, N. H., Emdin, S. O., Cajander, J., Landberg, G. (1997) Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein. Oncogene 14,295-304[Medline]
-
Molendini, L., Benassi, M. S., Magagnoli, G., Merli, M., Sollazzo, M. R., Ragazzini, P., Gamberi, G., Ferrari, C., Balladelli, A., Bacchini, P., Picci, P. (1998) Prognostic significance of cyclin expression in human osteosarcoma. Int. J. Oncol. 12,1007-1111[Medline]
-
Li, Z., Hromchak, R., Bloch, A. (1997) Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. Biochim. Biophys. Acta 1356,149-159[Medline]
-
Scott, K. A., Walker, R. A. (1997) Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer. Br. J. Cancer 76,1288-1292[Medline]
-
van Dierst, P., Michalides, R., Jannink, L., van der Valk, P., Peterse, H., de Jong, J., Meijer, C., Baak, J. (1997) Cyclin D1 expression in invasive breast cancer. Correlations and prognostic value. Am. J. Pathol. 150,705-711[Abstract]
-
Hirama, T., Koeffler, H. (1995) The role of cyclin-dependent kinase inhibitors in the development of cancer. Blood 86,841-854[Free Full Text]
-
Wakasugi, E., Kobayashi, T., Tamaki, Y., Nakano, Y., Ito, Y., Miyashiro, I., Komoike, Y., Miyazaki, M., Takeda, T., Monden, T., Monden, M. (1997) Analysis of phosphorylation of pRB and its regulatory proteins in breast cancer. J. Clin. Pathol. 50,407-412[Abstract/Free Full Text]
-
Hashimoto, Y., Kohri, K., Kaneko, Y., Morisaki, H., Kato, T., Ikeda, K., Nakanishi, M. (1998) Critical role for the 310 helix region of p57(Kip2) in cyclin-dependent kinase 2 inhibition and growth suppression. J. Biol. Chem. 273,16544-16550[Abstract/Free Full Text]
-
Orend, G., Hunter, T., Ruoslahti, E. (1998) Cytoplasmic displacement of cyclin E-cdk2 inhibitors p21Cip1 and p27Kip1 in anchorage-independent cells. Oncogene 16,2575-2583[Medline]
-
Wang, H., Shao, N., Ding, Q. M., Cui, J., Reddy, E. S., Rao, V. N. (1997) BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases. Oncogene 15,143-157[Medline]
-
Somasundaram, K., Zhang, H., Zeng, Y., Hovras, Y., Peng, Y., Zhang, H., Wu, G., Licht, J., Weber, B., El-Diery, W. (1997) Arrest of the cell cycle by the tumor-suppressor BRCA1 requires the CDK-inhibitor p21 WAF/Cip1. Nature (London) 389,187-190[Medline]
-
Lesaca, E. E., Ensley, J. F., Yeudall, W. A. (1998) Cellular factors may enable squamous carcinoma cells to overcome TGF beta-mediated repression of CDK2 activity. Oral Oncol 34,52-57[Medline]
-
Marches, R., Scheuermann, R. H., Uhr, J. W. (1998) Cancer dormancy: role of cyclin-dependent kinase inhibitors in induction of cell cycle arrest mediated via membrane IgM. Cancer Res 58,691-697[Abstract/Free Full Text]
-
Tanikawa, M., Yamada, K., Tominaga, K., Morisaki, H., Kaneko, Y., Ikeda, K., Suzuki, M., Kiho, T., Tomokiyo, K., Furuta, K., Noyori, R., Nakanishi, M. (1998) Potent prostaglandin A1 analogs that suppress tumor cell growth through induction of p21 and reduction of cyclin E. J. Biol. Chem. 273,18522-18527[Abstract/Free Full Text]
-
Desrivieres, S., Volarevic, S., Mercep, L., Ferrari, S. (1997) Evidence for different mechanisms of growth inhibition of T-cell lymphoma by phorbol esters and concanavalin A. J. Biol. Chem. 272,2470-2476[Abstract/Free Full Text]
-
Wu, X., Rubin, M., Fan, Z., DeBlasio, T., Soos, T., Koff, A., Mendelsohn, J. (1996) Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene 12,1397-1403[Medline]
-
Harvat, B. L., Seth, P., Jetten, A. M. (1997) The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. Oncogene 14,2111-2122[Medline]
-
Yasui, W., Kudo, Y., Semba, S., Yokozaki, H., Tahara, E. (1997) Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is associated with advanced stage and invasiveness of gastric carcinomas. Jpn. J. Cancer Res. 88,625-629[Medline]
-
Erlanson, M., Portin, C., Linderholm, B., Lindh, J., Roos, G., Landberg, G. (1998) Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas—prognostic implications. Blood 92,770-777[Abstract/Free Full Text]
-
Kwon, T. K., Nordin, A. A. (1998) Identification of cdk2 binding sites on the p27Kip1 cyclin-dependent kinase inhibitor. Oncogene 16,755-762[Medline]
-
St. Croix, B., Sheehan, C., Rak, J. W., Florenes, V. A., Slingerland, J. M., Kerbel, R. S. (1998) E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). J. Cell Biol. 142,557-571[Abstract/Free Full Text]
-
Sheaff, R. J., Groudine, M., Gordon, M., Roberts, J. M., Clurman, B. E. (1997) Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev 11,1464-1478[Abstract/Free Full Text]
-
Yamada, H., Ochi, K., Nakada, S., Takahara, S., Nemoto, T., Sekikawa, T., Horiguchi-Yamada, J. (1995) Interferon modulates the messenger RNA of G1-controlling genes to suppress the G1-to-S transition in Daudi cells. Mol. Cell. Biochem. 152,149-158[Medline]
-
Tiefenbrun, N., Melamed, D., Levy, N., Resnitzky, D., Hoffman, I., Reed, S. I., Kimchi, A. (1996) Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest. Mol. Cell. Biol. 16,3934-3944[Abstract]
-
Murakami-Mori, K., Mori, S., Nakamura, S. (1998) Endogenous basic fibroblast growth factor is essential for cyclin E-CDK2 activity in multiple external cytokine-induced proliferation of AIDS-associated Kaposi's sarcoma cells: dual control of AIDS-associated Kaposi's sarcoma cell growth and cyclin E-CDK2 activity by endogenous and external signals. J. Immunol 161,1694-1704[Abstract/Free Full Text]
-
Ikezawa, K., Ohtsubo, M., Norwood, T., Narayaran, A. (1998) Role of cyclin E and cyclin E-dependent kinase in mitogenic stimulation by cementum-derived growth factor in human fibroblasts. FASEB J 12,1233-1239[Abstract/Free Full Text]
-
Duronio, R. J., O'Farrell, P. H. (1995) Developmental control of the G1 to S transition in Drosophila: cyclin E is a limiting downstream target of E2F. Genes Dev 9,1456-1468[Abstract/Free Full Text]
-
Duronio, R. J., Brook, A., Dyson, N., O'Farrell, P. H. (1996) E2F-induced S phase requires cyclin E. Genes Dev 10,2505-2513[Abstract/Free Full Text]
-
Leng, X., Connell-Crowley, L., Goodrich, D., Harper, J. W. (1997) S-Phase entry upon ectopic expression of G1 cyclin-dependent kinases in the absence of retinoblastoma protein phosphorylation. Curr. Biol. 7,709-712[Medline]
-
Lukas, J., Herzinger, T., Hansen, K., Moroni, M. C., Resnitzky, D., Helin, K., Reed, S. I., Bartek, J. (1997) Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev 11,1479-1492[Abstract/Free Full Text]
-
Leone, G., DeGregori, J., Sears, R., Jakoi, L., Nevins, J. R. (1997) Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature (London) 387,422-426[Medline]
-
Sala, A., Kundu, M., Casella, I., Engelhard, A., Calabretta, B., Grasso, L., Paggi, M. G., Giordano, A., Watson, R. J., Khalili, K., Peschle, C. (1997) Activation of human B-MYB by cyclins. Proc. Natl. Acad. Sci. U. S. A. 94,532-536[Abstract/Free Full Text]
-
Zhao, J., Dynlacht, B., Imai, T., Hori, T., Harlow, E. (1998) Expression of NPAT, a novel substrate of cyclin E-CDK2, promotes S-phase entry. Genes Dev 12,456-461[Abstract/Free Full Text]
-
Seghezzi, W., Chua, K., Shanahan, F., Gozani, O., Reed, R., Lees, E. (1998) Cyclin E associates with components of the pre-mRNA splicing machinery in mammalian cells. Mol. Cell. Biol. 18,4526-4536[Abstract/Free Full Text]
-
Zerfass, K., Schulze, A., Spitkovsky, D., Friedman, V., Henglein, B., Jansen-Durr, P. (1995) Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J. Virol. 69,6389-6399[Abstract]
TOP
ABSTRACT
INTRODUCTION
