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: complex roles in cell proliferation and survival
Department of Biological Sciences, Hunter College of The City University of New York, New York, New York, USA
1Correspondence: Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Ave., New York, NY 10021, USA. E-mail: foster{at}genectr.hunter.cuny.edu
| ABSTRACT |
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(PKC
) has been implicated both as a tumor suppressor and a positive regulator of cell cycle progression. PKC
has also been reported to positively and negatively regulate apoptotic programs. This has led to conflicting hypotheses on the role of PKC
in the control of cell proliferation and survival. Surprisingly, PKC
mice develop normally and are fertile, indicating that PKC
is not critical for normal cell proliferation during development. However, PKC
may play important roles in neoplastic cell proliferation. In this review, we have summarized the apparent multifunctional properties of this enigmatic protein with regard to its role in the regulation of cell cycle progression and cell survival. It is proposed that PKC
has both tumor suppressor and proliferation capabilities that can be recruited as a backup kinase for both gatekeeper tumor suppression and as an activator of the Ras/Raf/MEK/MAP kinase signaling pathway in cell proliferation.Jackson, D. N., Foster, D. A. The enigmatic protein kinase C
: complex roles in cell proliferation and survival.
Key Words: cell cycle tumor promotion tumor suppressor tyrosine kinase
| INTRODUCTION |
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isoform of PKC where studies have implicated PKC
as a tumor suppressor and as a positive regulator of cell cycle progression. Adding to the confusion, PKC
has been reported to both positively and negatively regulate apoptosis (6)
in the regulation of cell cycle progression and survival.
PKC NULL MICE
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in cell proliferation, it is important to mention studies of PKC
null mice. Two separate groups have generated PKC
null mice strains (7
is not required for cell proliferation during normal development. Although these mice did not show obvious increases in cancer, they had significantly higher numbers of smooth muscle cells than were found in wild-type animals, which correlated with decreased smooth muscle cell death (7)
null aortas were also resistant to cell death induced by several stimuli (7)
is critical for certain stress responses. Also found in the PKC
null mice were increased proliferation of B cells and autoimmunity (8)
is not required for the proliferation of normal cells. Phenotypes shown by the PKC
null mice are similar to that observed in mice with a defect in the tumor suppressor p53, which were also susceptible proliferative disorders (9)
may act as a tumor suppressor under certain conditions is addressed below. | REGULATION OF CELL PROLIFERATION |
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as a negative regulator of cell cycle progression
on cell proliferation have found that PKC
inhibits cell proliferation. However, as discussed below, several studies have found that PKC
is required for the proliferation of some transformed and cancer cells. We will first describe studies that have shown an inhibitory effect of PKC
on cell proliferation. Watanabe et al. (10)
on cell proliferation in CHO cells. Mischak et al. (11)
inhibited proliferation of NIH 3T3 mouse fibroblasts. Acs et al. (12)
suppresses NIH 3T3 cell proliferation, but a mutation at Tyr155 of PKC
led to increased proliferation. This study provided an interesting insight into the ability of PKC
to both positively and negatively regulate cell proliferation possibly through the differential phosphorylation of PKC
on tyrosines. The potential role of tyrosine phosphorylation is addressed further below. PKC
has also been shown to inhibit the proliferation of neonatal rat cardiac fibroblasts (13)
to negatively affect cell proliferation in culture. Recently, Kambhampati et al. (14)
in leukemic and MCF-7 cells, indicating that endogenously expressed PKC
can suppress cell proliferation.
Several studies have examined the effect of PKC
on cell cycle progression. PKC
was shown to inhibit the proliferation of rat vascular smooth muscle cells (15)
; FACS analysis indicated that these cells were blocked with a G0/G1 DNA content, indicating that cells were prevented from entering S-phase. Consistent with this finding, expression of G1 cyclins was suppressed by elevated expression of PKC
(15)
. PKC
also inhibited progression into S-phase of capillary endothelial cells (16
, 17)
. A431 cells were blocked at the G1/S transition by an anti-tumor somatostatin analog in a mechanism that required PKC
(18)
, demonstrating that the G1 block was not an artifact of elevated expression of PKC
. Similarly, induction of the G1 cyclin-dependent kinase inhibitor, p21Cip1, by epidermal growth factor (EGF) in A431 cells was dependent on PKC
(19)
. PKC
was required for expression of p21Cip1 in rat aortic smooth muscle cells (20)
and MCF-7 cells (21)
. PKC
inhibited expression of the G1 cyclin (cyclin D1) in vascular smooth muscle cells (15)
and in NIH 3T3 cells (22)
, and PKC
inhibited cyclin D1 promoter activity in primary bovine airway smooth muscle cells (23)
. Thus, PKC
suppresses cell cycle progression into S-phase, at least in part, by inhibiting G1 cyclin expression and increasing expression of cyclin-dependent kinase inhibitors.
In addition to blocking progression into S-phase, elevated expression of PKC
led to cell cycle arrest at the G2/M checkpoint in CHO cells (10)
. Kitamura et al. (24)
reported that PKC
suppressed entrance to M-phase in 3Y1 rat fibroblasts. Bistratene A, which activates PKC
with some specificity (25)
, induced cell cycle arrest at G2/M in a human melanoma cell line (26)
. These studies suggest that PKC
is able to provide a "gatekeeper" function that prevents cell cycle progression through G1/S and G2/M cell cycle checkpoints.
PKC
as a positive regulator of cell proliferation
Although a majority of studies of the effect of PKC
on cell proliferation suggest that PKC
suppresses proliferation, several reports have demonstrated a positive role for PKC
in cell proliferation. PKC
was required for insulin-like growth factor-I (IGF-I), receptor-mediated cell transformation, most likely via an association between the IGF-1 receptor and PKC-
and activation via tyrosine phosphorylation (27)
. Consistent with a role for PKC
in IGF-I signaling, the von-Hippel-Lindau tumor suppressor pVHL interacted directly with PKC
in renal cell carcinoma cell lines and inhibited a required association between PKC
and the IGF-I receptor for downstream signaling (28
, 29)
. Thus, there appears to be a PKC
requirement in proliferation signals mediated by the IGF-I receptor in transformed and cancer cells. Does PKC
play a physiological role in signaling through the IGF-I receptor? It would seem unlikely since IGF-I receptor null mice exhibit severe developmental abnormalities and die within minutes of birth (30
, 31)
, whereas PKC
null mice develop normally (7
, 8)
. If PKC
were required for normal IGF-I receptor-mediated signaling, it would be expected that PKC
null mice would have a phenotype similar to the IGF-I receptor null mice. It is still possible, however, that since the IGF-I receptor can activate multiple intracellular signals, a compensatory signal that overcomes the need for PKC
could be activated in the PKC
null mice. PKC
was not required for the anti-apoptotic effects of IGF-I on cultured myocytes (32)
, indicating that PKC
is not required for this particular effect of IGF-I on normal cells. We would suggest that under conditions where the IGF-I receptor is overexpressed or the VHL gene is not present, the IGF-I receptor most likely is able to co-opt PKC
and utilize it to activate mitogenic signals. Thus, while PKC
may not play a critical role in normal cell proliferation, PKC
may be critical for the proliferation of some cancers such as renal cell carcinoma.
Consistent with a positive role for PKC
in some transformed cells, Jaken and co-workers have reported increased levels of PKC
in progressively transformed rat embryo fibroblasts and that a dominant negative PKC
could block anchorage independent growth of these cells (33)
. This group has also showed a correlation between PKC
expression and metastatic potential in breast cancer cell lines and that elevated expression of PKC
led to increased anchorage-independent growth of the poorly metastatic cells (34)
. Inhibiting PKC
also inhibited the metastatic potential of breast cancer cells (35)
. Consistent with these observations, PKC
was required for the migration of breast cancer cells with elevated expression of the EGF receptor (36)
. PKC
was reported to act as a prosurvival factor in the MCF-7 human breast cancer cell line in vitro (37)
. Inhibition of PKC
in these cells decreased survival in response to radiation-induced DNA damage, indicating that PKC
was able to provide a survival signal. PKC
can interact positively with mTOR (38)
, which has also been implicated in survival signaling (39)
. It remains to be determined whether survival signals generated by PKC
in MCF-7 cells are dependent on mTOR.
Inhibition of PKC
was reported to prevent estrogen-induced, mitogen-activated protein kinase (MAPK) activation while having no effect on transforming growth factor-
-induced MAPK activation in MCF-7 human breast cancer cells (40)
. This study revealed that the activation of MAPK by estrogen was mediated through a HER-2/PKC
/Ras pathway. These data suggest that the estrogen receptor-positive MCF-7 cell line has used PKC
to activate MAPK and that this may prevent apoptosis in these cells. Since MAPK is activated in response to most, if not all, mitogenic signals, the ability of PKC
to activate MAPK (40
, 41)
may be an important component of PKC
s ability to positively regulate cell proliferation and survival. What is not clear is why and under what circumstances PKC
activates MAPK. Although PKC
apparently can be co-opted into oncogenic signaling pathways, aside from the interesting observation that a Tyr
Phe mutation at Tyr155 stimulate proliferation of NIH 3T3 cells (12)
, there is no evidence that elevated expression of wild-type PKC
itself can stimulate cell proliferation or activate an oncogenic signal. It is therefore doubtful that PKC
can act as an oncogene, however it may act as a partner to an oncogene or as a "co-oncogene" under some circumstances, such as renal cell carcinoma, where the VHL gene is lost.
The ability of PKC
to act as a co-oncogene may be the result of its ability to activate MAPK, a critical target of mitogenic signaling through the Ras/Raf/MEK/MAPK signal transduction pathway. An activated mutant of PKC
was reported to activate MAPK in a mechanism that is independent of Ras, but dependent on Raf and MEK (41)
. In contrast, the PKC
-dependent activation of MAPK by estrogen was dependent on Ras (40)
. The PKC
-dependent activation of MAPK by neurogenic agents, including fibroblast growth factor (FGF) was dependent on MEK, but not Raf (42)
. Similarly, FGF-induced MAPK in rat pituitary tumor cells was independent of Ras and Raf (43)
. Thus, it would seem that PKC
can contribute to MAPK activation at several points in the Ras/Raf/MEK/MAPK signaling pathway: 1) upstream of Ras (40)
; 2) downstream of Ras but upstream of Raf (41)
; and 3) downstream of Raf but upstream of MEK (42)
. The ability of PKC
to activate the MAPK pathway at different places is shown schematically in Fig. 1
. How PKC
can activate MAPK using several apparently different mechanisms is not clear.
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| TYROSINE PHOSPHORYLATION |
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to perform very different tasks under different conditions leads to the question: How this is accomplished? A likely explanation is the ability of PKC
to associate with different tyrosine kinases resulting in differential patterns of phosphorylation on the tyrosine residues of PKC
. PKC
has been reported to associate with Src (44
is able to interact with the IGF-I receptor in cancerous and transformed cells (27
becomes phosphorylated on different tyrosines in response to different stimuli, and the effect of tyrosine phosphorylation has been reported to have many effects on PKC
. There are 19 tyrosines in PKC
, and at least 9 have been implicated as sites that become phosphorylated. Tyrosine phosphorylation on PKC
has been discussed in two reviews (6
as might be expected for a protein that can apparently be phosphorylated at so many different sitesis complex and confusing.
Of particular relevance for the role of PKC
in regulating cell proliferation is that tyrosine kinase activity is commonly elevated in response to mitogenic and oncogenic signals (52)
and that PKC

frequently phosphorylated on tyrosine in response to mitogenic and other stimuli. Tyrosine phosphorylation of PKC
was first reported in keratinocytes expressing oncogenic H-Ras (53)
. The tyrosine phosphorylation on PKC
rendered PKC
insensitive to TPA, indicating that tyrosine phosphorylation was inhibiting PKC
kinase activity. Src was able to phosphorylate PKC
on tyrosine in vitro, but this phosphorylation was reported to increase PKC
activity (54)
. PKC
associates with activated Src and is phosphorylated on tyrosine (44)
, but the tyrosine-phosphorylated PKC
in these cells, like that in H-Ras-transformed cells, showed reduced kinase activity. TPA treatment of MCF-7 cells led to the association of PKC
and activated c-Src (46)
. Tamoxifen also stimulated an association between c-Src and PKC
that led to the tyrosine phosphorylation of PKC
(48)
. Tamoxifen treatment led to a reduction in PKC
protein levels (48)
. PKC
was reported to be tyrosine-phosphorylated in response to TPA, and the authors reported that tyrosine phosphorylation by Src family kinases led to increased kinase activity (55)
. Blake et al. (45)
also reported an association between activated Src and PKC
that led to tyrosine phosphorylation in NIH-3T3 cells, but this led to elevated activity. Tyrosine-phosphorylated PKC
, however, was less stable and reduced levels of PKC
were observed in the cells with expression of activated Src (45)
. A Tyr
Phe mutation at Tyr311 blocked tyrosine-phosphorylation of PKC
and led to the stabilization of PKC
, suggesting that activated Src phosphorylates PKC
at Tyr311 and that phosphorylation at this site enhances degradation (45)
.
PDGF stimulated the tyrosine phosphorylation of PKC
(56)
, which was subsequently shown to occur at Tyr187 (57)
. Phosphorylation of PKC
at this site did not appear to affect the activity; however, elevated expression of PKC
blocked PDGF-induced DNA synthesis (45)
. Tyrosine phosphorylation of PKC
in response to transforming growth factor-
and EGF led to decreased activity of PKC
(58)
. It was suggested that since the receptors did not phosphorylate PKC
in vitro, the phosphorylation was probably due to indirect stimulation of Src family kinases. In addition to Src, both Lyn and Fyn have been reported to interact with and phosphorylate PKC
. Lyn phosphorylates PKC
at Tyr52, leading to an association between the Lyn SH2 domain and PKC
(47)
. Activation of human platelets led to a functional association between Fyn and PKC
(59)
, and Fyn was shown to associate with phosphorylated Tyr187 of PKC
(12)
. Unlike other tyrosine kinase receptors, activated IGF-I receptor was able to phosphorylate PKC
in vitro (27)
.
IgE stimulation of leukemia cells led to the phosphorylation of PKC
at Tyr52 (60)
. IgE-stimulated tyrosine phosphorylation reduced activity toward some, but not all, substrates, leading the investigators to propose that tyrosine phosphorylation modifies substrate recognition (61)
. This important observation indicated how differential tyrosine phosphorylation could be critical for the reported differential effects of PKC
.
In response to ionizing radiation (50)
and oxidative stress (62)
, PKC
is phosphorylated by c-Abl. Oxidative stress leads to tyrosine phosphorylation of PKC
(63)
. Sites 512 and 523 in the catalytic domain were critical for activation of PKC
by H2O2; subsequent studies using mass spectrometry revealed that sites 311, 323, and 512 were the sites actually phosphorylated in response to H202 and phosphorylation at Tyr311 was apparently the most critical for increased activity (64)
. Etoposide also induced tyrosine phosphorylation of PKC
, and sites 64 and 187 were critical for this effect (65)
.
Anti-sense PKC
inhibited differentiation of mouse keratinocytes whereas overexpression of PKC
in the presence of a Src kinase inhibitor enhanced differentiation (66)
. Plasmids encoding phenylalanine mutants of PKC
tyrosine residues 64 and 565 induced differentiation in the absence of an Src inhibitor, suggesting that phosphorylation of these sites by Src suppressed differentiation. In contrast, phenylalanine mutants of tyrosine residues 52, 155, and 187 were inactive, indicating these sites are required for differentiation. Thus, Src kinase mediated post-translational modification of PKC
on specific tyrosine residues in mouse keratinocytes apparently suppresses PKC
-mediated differentiation.
Many of the phosphorylation site studies have used Tyr
Phe mutations to block tyrosine phosphorylation and thus implicate various sites as critical sites of tyrosine phosphorylation. It is possible that a mutation at a particular site blocks phosphorylation at other sites. Thus, it is not always clear which and how many sites are actually phosphorylated in response to a given stimulus. The ability to alter substrate specificity and phenotype with these mutations indicates that the many permutations of differential tyrosine phosphorylation by different tyrosine kinases in response to different stimulation would provide PKC
the ability to be used in many different ways under different circumstances. The reported differential effects of tyrosine phosphorylation on the activity of PKC
have also suggested that PKC
can be manipulated in different ways through tyrosine phosphorylation. However, the PKC
activity assays are performed in vitro and may not reflect the actual in vivo activity. There remains much to be learned about the apparent multiple effects of tyrosine phosphorylation on PKC
activity, substrate specificity, and subcellular localization. Table 1
summarizes the available data on the tyrosines phosphorylated on PKC
and the effects of phosphorylation.
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PKC AS A TUMOR SUPPRESSOR
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could contribute to a transformed phenotype came when it was shown that down-regulating PKC
with prolonged TPA treatment transformed rat fibroblasts with elevated expression of the Src tyrosine kinase (67)
to transform rat fibroblasts (68)
down-regulation, in concert with elevated tyrosine kinase expression, to cause transformation led to the conclusion that the tumor-promoting effects of phorbol esters are due largely to the down-regulation of a tumor-suppressing effect of PKC
(67
in their skin. These mice were resistant to the tumor-promoting effects of phorbol esters in the standard mouse skin carcinogenesis assay originally used to define the tumor promoting effects of phorbol esters (69)
from down-regulation (71)
isoform of PKC. Although the existing data strongly support the hypothesis that suppression of PKC
by phorbol esters are critical for the tumor promotion, positive effects on other PKC isoforms cannot be ruled out.
Consistent with a tumor suppressing effect for PKC
, the PKC
inhibitor rottlerin (73)
was shown to induce a transformed phenotype in human keratinocytes (74)
, further implicating PKC
as suppressor of transformation. Rottlerin was able to induce a transformed phenotype in rat fibroblasts overexpressing either c-Src or the EGF receptor (67
, 68)
. Perletti et al. (75)
reported reduced levels of PKC
in rat colonic epithelial cells transformed by Src. This group went on to show that elevated PKC
expression in these cells suppressed the Src-induced transformed phenotype. Moreover, a dominant negative PKC
mutant was able to induce a partial transformed phenotype in rat colonic epithelial cells (75)
. Transient transfection of NIH3T3 cells with a dominant negative PKC
mutant induced a transformed phenotype (76)
. Inhibition of PKC
was able to abolish contact inhibition in human and murine fibroblasts (76)
. Immunofluorescence revealed a rapid translocation of PKC
to the nucleus when cultures reached confluence with a peak in early-mid G1 phase (76)
. These data suggested that the suppression of growth in response to cellcell contact may be due to PKC
substrates in the nucleus. Nuclear translocation of PKC
to the nucleus is also required for etoposide-induced apoptosis (77)
. Collectively, these studies suggested that PKC
has the potential to suppress cell proliferation and act as a tumor suppressor.
The ability of PKC
down-regulation to cooperate with elevated expression of a tyrosine kinase is consistent with a model for transformation of primary cells postulated by Weinberg and colleagues (78)
. In their model, an oncogene that provides the equivalent of growth factor signal such as Ras or Src cooperates with Myc or large T antigen to transform primary cells. TPA was shown to cooperate with Ras to transform primary cells (79)
. It is reasonable this cooperation was due to TPA-induced down-regulation of PKC
.
A model for complementing transforming and tumor-suppressing genes is presented in Fig. 2
. In this model, complementing transforming or tumor-suppressing genes are designated class I or class II oncogenes based on whether they facilitate passage through the restriction point (80)
, or through cell cycle checkpoints that monitor the readiness of cells to progress into a new phase of the cycle (81)
. The class I oncogenes mimic growth factor signals that facilitate passage through the growth factor-dependent restriction point (80)
. The early G1 phase prior to the restriction point has been referred to as the G1 PM(postmitotic) phase (82)
. The absence of growth factors stimulates exit from G1-pm to a quiescent G0 state (81
, 83)
and class I genes such as an activated Ras gene or a tyrosine kinase provide growth factor independence and avoid cell cycle exit to G0 and quiescence. The class II genes, in contrast, facilitate progression through cell cycle checkpoints and, most important, through the later part of G1 after the restriction point, referred to as the G1-ps (pre-S) phase (82)
, and require cyclins that along with their partner kinases prevent the inhibitory function of Rb (84)
. In this model, the ability of PKC
down-regulation to complement elevated expression of a tyrosine kinase (67
, 68)
would suggest that PKC
down-regulation is providing the equivalent of class II genes that facilitate progression through cell cycle checkpoints. Thus, down-regulating PKC
is apparently able to provide what T antigen accomplishes. T antigen sequesters and inactivates p53 and Rb (85)
, both of which block passage through cell cycle checkpoints. Consistent with a role for PKC
down-regulation in progression through cell cycle checkpoints, expression of G1 cyclins was suppressed by elevated expression of PKC
(15
, 22)
. Moreover, PKC
was required for expression of the G1 cyclin inhibitor p21Cip1 in rat aortic smooth muscle cells (20)
and MCF-7 cells (21)
. Elevated expression of PKC
also led to cell cycle arrest at the G2/M checkpoint in CHO cells (10)
and rat fibroblasts (24)
. Preliminary data indicate that PKC
is required for DNA damage induced increases in p53 expression and concomitant apoptosis (86)
. The ability of PKC
to suppress the expression of factors required for progression through cell cycle checkpoints indicates that PKC
has gatekeeper functions similar to those of other known tumor suppressor genes, such as Rb and p53.
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| STRESS RESPONSE AND APOPTOSIS |
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with an apparent gatekeeper function has been implicated in apoptosis. The role that PKC
plays in apoptosis appears to be as complicated as the role it plays in cell proliferation. A large body of evidence implicates PKC
in apoptotic responses; as with cell proliferation, however, PKC
seems to have been co-opted in some cancer cells to be anti-apoptotic. Brodie and Blumberg (6)
in apoptosis, and we will not attempt to expand on their review other than to highlight an emerging paradigm whereby PKC
is a critical component of the cellular stress response. PKC
is activated in response to a variety of genotoxic stress (6)
is cleaved to a 40 kDa catalytically active fragment by caspase-3 (88)
catalytic fragment induced chromatin condensation and DNA fragmentation, indicating a role for PKC
cleavage in the induction of apoptosis (89)
catalytic fragment generated in response to DNA damage (90)
also apparently is required for basal transcription levels of the p53 tumor suppressor gene (86)
interacts with c-Abl in response to genotoxic stress and is phosphorylated on tyrosine (50)
was recently shown to be critical for the response to mechanical stress in smooth muscle cells (91)
in cellular stress responses and show that in some cases PKC
is required for apoptosis. Thus, cell survival can depend on the regulation of PKC
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DOES PKC PLAY A ROLE IN HUMAN CANCER?
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in human cancer has not been clearly established, but it is of interest that the human PKC
gene is located on chromosome 3p (92)
is located at 3p14 (92)
could play a role in breast cancer progression. Down-regulation of PKC
cooperates with overexpression of tyrosine kinase to transform cells and overexpression of tyrosine kinases is observed more often in breast cancer than any other tumor type (52)
activity in breast epithelial cells that have acquired a mutation that elevates expression of a tyrosine kinase could contribute to tumor progression.
As described, PKC
may also contribute to the proliferation in renal cell carcinoma and breast cancer. The tumor suppressor VHL interacts directly with PKC
in renal cell carcinoma cells and inhibits association between PKC
and the IGF-I receptor for downstream signaling (28
, 29)
. Expression of PKC
in breast cancer cell lines correlated with their metastatic potential, and elevated expression of PKC
led to increased anchorage-independent growth of poorly metastatic cells (34
, 35)
. PKC
was also reported to promote cell survival and chemotherapeutic resistance in non-small cell lung cancer cells (95)
. Elevated expression of PKC
was also reported in multiple myeloma cells, and its down-regulation caused apoptosis (96)
. PKC
has been shown to interact with MUC1 (97)
, and the stimulatory effects of MUC1 on anchorage-independent growth were abrogated by mutation of the PKC
phosphorylation site (97)
. Since MUC1 is elevated in a variety of cancers, a requirement for PKC
to stimulate anchorage-independent growth provides evidence that PKC
may stimulate proliferation in cancers driven by MUC1. Thus, there is evidence that PKC
may play both positive and negative roles in the control of neoplastic proliferation and survival.
| CONCLUSIONS |
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is capable of influencing cell proliferation both positively and negatively. PKC
has also been reported to both positively and negatively influence apoptosis (6)
on cell proliferation and survival be reconciled? Surprisingly, results with PKC
null mice revealed that mice lacking PKC
developed normally and were fertile (7
null mice, however, had some hyperproliferative phenotypes that could correlate with the role that PKC
plays in suppression of cell proliferation and apoptosis (6)
is not required for normal cell proliferation during development. Why, then, is PKC
so widely expressed in so many tissues, and why does PKC
turn up so often as a critical regulator of proliferative responses. We would propose that PKC
is a critical stress response gene that can provide backup support for both proliferative and nonproliferative crises. PKC
has the properties of a tumor suppressor that prevents inappropriate cell proliferation under some stressful conditions. Consistent with a tumor suppressor function for PKC
, mice strains with knockouts of other tumor suppressor genes have phenotypes similar to the PKC
null mice in that they develop normally, but develop proliferative disorders (9)
that have been reported in many transformed and cancer cells? While PKC
-dependent proliferation in normal cells has not been reported, the IGF-I receptor can apparently stimulate PKC
-dependent proliferation in transformed and cancer cells. It is possible that the ability of PKC
to activate the critical MAPK pathway by several different mechanisms (Fig. 1
is a multitasking kinase that can be co-opted into variety of cellular functions that largely protect the cell from cancer, but also from a lack of needed proliferation. That such a protein, capable of both anti- and pro-proliferative signals, is also involved in apoptosis makes sense. If there is an inappropriate co-opting of PKC
leading to either neoplastic or degenerative disease, PKC
can be cleaved by caspase 3 to a catalytic fragment capable of stimulating apoptosis (88
as a stress response protein that can function as a backup for tumor suppressor and proliferation functions is presented in Fig. 3
, clearly much needs to be learned about how PKC
participates in the varied and sometimes contradictory effects seen with this enigmatic protein.
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| ACKNOWLEDGMENTS |
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in cell proliferation. We would also like to thank Lu-Hai Wang for comments on the manuscript. We acknowledge the support to the laboratory from the National Cancer Institute, and institutional support from the Research Centers in Minority Institutions (RCMI) program of the National Institutes of Health. Received for publication October 3, 2003. Accepted for publication December 10, 2003.
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