Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor-suppressor protein p53 has been implicated in cell cycle arrest and apoptotic cell death in dividing cells (Yonish-Rouach et al. [1991] Nature 352:342-347. To elucidate possible functions of p53 in the regulation of cell division and cell death during development of the rat central nervous system, we compared the spatial and temporal expressions of p53 mRNA and protein with those of its transcriptional targets Bax, p21Waf1, and cyclin G1 and with the cyclin-dependent kinase inhibitors p27Kip1, p57Kip2, and p16Ink4a. From embryonic day 14 until the second postnatal week, p53 mRNA and protein were found predominantly in proliferating zones, including the cells of the emerging external granular layer of the cerebellum, and the ventricular and the subventricular zones of the forebrain. At all postnatal ages, there was a high expression of p53 mRNA and protein in cells of the rostral migratory stream, a well-defined pathway along which precursor cells of olfactory interneurons migrate from the ventricular and subventricular zones toward the olfactory bulb. In addition to its expression in proliferating cell populations, p53 was expressed in postmitotic cells of the cerebral cortex and hippocampus at embryonic and early postnatal stages. p53, p27Kip1, p16Ink4a, and bax alpha mRNA colocalized in the ventricular and subventricular zones at embryonic and early postnatal stages, but the distribution of p53 differed from that of its transcriptional targets cyclin G1 and p21Waf1 and from that of the cyclin-dependent kinase inhibitor p57Kip2, which were predominantly expressed in fully differentiated neurons. Double-labeling studies showed that p53 mRNA and protein were absent in cells undergoing developmental cell death, as identified by the presence of single- or double-stranded nuclear DNA breaks. Protein levels of p53 decreased during development in all brain areas studied. These results indicate a role for p53 in the control of cell division and early differentiation rather than in the control of cell death during rat brain development. The nonoverlapping temporal and spatial expression patterns of p53 and its transcriptional targets Bax, cyclin G1 and p21Waf1 suggest that each of these gene products fulfill independent roles in brain morphogenesis.
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PMID:Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: comparison with expression of the cell cycle regulators p21Waf1/Cip1, p27Kip1, p57Kip2, p16Ink4a, cyclin G1, and the proto-oncogene Bax. 965 83

The molecular mechanism of androgen-independent growth of prostate cancer after androgen ablation was explored in LNCaP cells. An androgen-dependent clonal subline of the LNCaP human prostate carcinoma cell line, LNCaP 104-S, progressed to a slow growing stage (104-R1) and then to a faster growing stage (104-R2) during more than 2 yr of continuous culture in the absence of androgen. Androgen-induced proliferation of 104-S cells is inhibited by the antiandrogen Casodex, while proliferation of 104-R1 and 104-R2 cells is unaffected by Casodex. This indicates that proliferation of 104-R1 and 104-R2 cells is not supported by low levels of androgen in the culture medium. Compared with LNCaP 104-S cells, both 104-R1 and 104-R2 cells express higher basal levels of androgen receptor (AR), and proliferation of these two cell lines is paradoxically repressed by androgen. After continuous passage in androgen-containing medium, 104-R1 cells reverted back to an androgen-dependent phenotype. The mechanism of androgenic repression of 104-R1 and 104-R2 sublines was further evaluated by examining the role of critical regulatory factors involved in the control of cell cycle progression. At concentrations that repressed growth, androgen transiently induced the expression of the cyclin-dependent kinase (cdk) inhibitor p21waf1/cip1 in 104-R1 cells, while expression of the cdk inhibitor p27Kip1 was persistently induced by androgen in both 104-R1 and 104-R2 cells. Induced expression of murine p27Kip1 in 104-R2 cells resulted in G1 arrest. Specific immunoprecipitates of Cdk2 but not Cdk4 from androgen-treated 104-R1 cells contained both p21waf1/cip1 and p27Kip1. This observation was confirmed by in vitro assay of histone H1 and Rb (retinoblastoma protein) phosphorylation by the proteins associated with the immune complex. Furthermore, inhibition of Cdk2 activity correlated with the accumulation of p27Kip1 and not p21waf1/cip1. From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation.
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PMID:Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. 965 99

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.
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PMID:Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor. 966 78

In the present study we analyzed, by immunohistochemistry, a panel of human melanomas for protein expression of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 and evaluated whether deregulated expression correlates with clinical outcome for this type of cancer. We found that p27Kip1 was strongly expressed by normal melanocytes and benign nevi, whereas in malignant melanoma, a heterogeneous expression pattern was observed. In the case of nodular melanomas, the level of p27Kip1 was found to correlate significantly with the thickness of the tumor, with less protein expressed in thicker lesions. We also found that patients having tumors with fewer than 5% p27Kip1-staining cells had a significantly higher risk of early relapse of their disease compared with those expressing moderate or high levels. In contrast, the level of p27Kip1 did not correlate with tumor thickness or disease-free survival in patients with superficial spreading melanomas, suggesting that p27Kip1 may play different roles in these two major pathological subgroups of malignant melanoma. Furthermore, p27Kip1 did not appear to have an influence on overall survival for either subgroup. When we examined the combined effect of p21WAF1/CIP1 (another cdk inhibitor) and p27Kip1 on clinical outcome, we found that analysis of these two cdk inhibitors together may have greater prognostic potential than either alone. In conclusion, our results suggest that virtually complete loss of p27Kip1 protein expression has potential importance as a prognostic indicator of early relapse in patients with nodular melanoma The results, furthermore, underscore the value of analyzing multiple cell cycle regulatory proteins to obtain the most reliable indication of prognosis.
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PMID:Protein expression of the cell-cycle inhibitor p27Kip1 in malignant melanoma: inverse correlation with disease-free survival. 966 92

Our previous data demonstrated that Ras activation is necessary and sufficient for transforming growth factor beta (TGFbeta)-mediated Erk1 activation, and is partially required for the inhibition of cyclin-dependent kinase 2 (Cdk2) activity, cyclin A expression and DNA synthesis by TGFbeta (KM Mulder and SL Morris, J. Biol. Chem., 267: 5029-5031, 1992; MT Hartsough and KM Mulder, J. Biol. Chem., 270: 7117-7124, 1995; and MT Hartsough et al., J. Biol. Chem., 271: 22368-22375, 1996). Here, we examined the kinetics and role of Ras in TGFbeta3-mediated effects on specific G1 cell cycle components in TGFbeta-sensitive (4-1) and TGFbeta-resistant (4-6) intestinal epithelial cells (IEC's). Our results indicate that inactivation of Ras by stable, inducible expression of a dominant-negative mutant of Ras (RasN17) completely abrogated the ability of TGFbeta3 to up-regulate both CKI's. In contrast, the ability of TGFbeta3 to up-regulate p27Kip1 and p21Cip1 was maintained in ZnCl2-treated control cells. Inactivation of Ras also completely blocked the rapid TGFbeta-mediated increase in new synthesis of p27Kip1 protein. Moreover, up-regulation of p21Cip1 protein levels and new synthesis of p27Kip1, as well as the association of these CKI's with Cdk2, preceded the decrease in Cdk2 activity by TGFbeta. Collectively, our results suggest that p21Cip1 and p27Kip1 are upstream effectors of the TGFbeta-mediated inhibition of Cdk2 activity in IEC 4-1 cells, and demonstrate that Ras activation is obligatory for TGFbeta-mediated up-regulation of these CKIs in untransformed epithelial cells.
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PMID:Blockade of TGFbeta3 up-regulation of p27Kip1 and p21Cip1 by expression of RasN17 in epithelial cells. 967 13

p27Kip1, one of the cyclin-dependent kinase (CDK) inhibitors (CDKIs), blocks progression from G1 to S phase by binding cyclin D1-CDK4 and/or cyclin E-CDK2 and inhibiting their activities. Reflecting the function of p27 as a CDKI in vitro, a reduced expression of protein p27 has recently been reported to be associated with tumor aggressiveness in some types of human cancers. In the present study, we examined the relationships between immunohistochemically detected expression of p27, cyclin D1, cyclin E proteins and clinicopathological findings in 77 patients with esophageal squamous cell carcinoma (SCC). Using specific monoclonal antibodies to p27, cyclin DI and cyclin E proteins, positive immunostaining in the nuclei was observed in 32.5% (25/77), 27.3% (21177) and 29.6% (21/71) of patients, respectively. There were no statistically significant relationships among the expressions of these 3 proteins. Using the Kaplan-Meier's method, p27 and cyclin D1 expressions were found to be independently associated with poor prognosis. When all parameters were combined into a multivariate regression analysis using the Cox model, the expressions of p27 and cyclin D1 retained a predictive value for survival. In contrast to former reports supporting a tumor-suppressive function of p27, our results suggest that altered expression of p27 and cyclin D1 may be associated with the progression of human esophageal SCC, in which cyclin E may well not play any central role.
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PMID:Positive correlation between p27Kip1 expression and progression of human esophageal squamous cell carcinoma. 969 40

The chemotherapeutic agent and vitamin A metabolite retinoic acid (RA) has been used to treat many tumor types. The effects of RA are mediated by a family of ligand-dependent transcription factors, the RA receptors and the retinoid X receptors (RXR). Alterations in retinoid receptor expression have been implicated in tumorigenesis. Previous studies have shown lack of RXR-gamma expression in squamous cell carcinoma (SCC) lines. To begin to elucidate the role of RXR-gamma in the malignant transformation of SCCs, we expressed RXR-gamma in SCC lines by stable transfection. SCC lines expressing RXR-gamma produced large numbers of flat cells with abundant cytoplasm, which died and detached from the culture dish. These cells morphologically resembled the differentiated cells of normal stratified squamous epithelium in culture. These cells did not exhibit the characteristic DNA fragmentation pattern of apoptotic cells, nor did they label in a fluorescent apoptosis assay. RNase protection and Western blot analysis revealed induction of RA-responsive involucrin and keratin 10 expression, early markers of terminal differentiation. RXR-gamma expression produced significant reduction in levels of RA-responsive genes including the cyclin-dependent kinase inhibitors p21Cip1/WAF1 and p27Kip1, resulting in increased cdc2 and cdk2 kinase activity and RB phosphorylation. We concluded that RXR-gamma induced terminal differentiation in SCC lines, suggesting a potential tumor suppressor function for this transcription factor.
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PMID:Increased cdc2 and cdk2 kinase activity by retinoid X receptor gamma-mediated transcriptional down-regulation of the cyclin-dependent kinase inhibitor p21Cip1/WAF1 correlates with terminal differentiation of squamous cell carcinoma lines. 971 79

The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19 INK4d protein has been determined at 1.9 A resolution. The results provide the first structural information for a cyclin D-dependent protein kinase and show how the INK4 family of CDK inhibitors bind. The structure indicates that the conformational changes induced by p19INK4d inhibit both productive binding of ATP and the cyclin-induced rearrangement of the kinase from an inactive to an active conformation. The structure also shows how binding of an INK4 inhibitor would prevent binding of p27Kip1, resulting in its redistribution to other CDKs. Identification of the critical residues involved in the interaction explains how mutations in Cdk4 and p16INK4a result in loss of kinase inhibition and cancer.
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PMID:Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d. 975 Oct 51

A cyclin-dependent kinase (cdk) inhibitor, p27Kip1 (p27), binds to the cyclin E-cdk2 complex and functions as a suppressor of cell cycle promotion. Here, the involvement of p27 in the growth of normal human endometrium was immunohistochemically studied, and the findings were compared with those of Ki-67, cyclin E and cdk2. In addition, to elucidate the effect of progesterone on the expression of p27, tissues from patients with endometrial hyperplasia were examined before and after the administration of medroxyprogesterone acetate (MPA) for the treatment of this disease. In the glandular cells of the normal endometrium, p27 was negligible during the proliferative phase, whereas it was markedly increased in the secretory phase. The staining pattern of Ki-67 was the reverse. Cyclin E/cdk2-positive cells were observed throughout the menstrual cycle. In the secretory phase, the cyclin E/cdk2-positive cells were also positive for p27, suggesting an interaction between these molecules. Stromal cells, especially in the basalis, showed a consistent expression of p27 throughout the menstrual cycle. The expression of p27 in hyperplastic epithelia before the MPA treatment was negligible, whereas it was greatly increased after the treatment. The Ki-67 positivity decreased after the treatment. These findings suggest that p27 is involved in the progesterone-induced growth suppression of normal and hyperplastic endometria.
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PMID:Involvement of cyclin-dependent kinase inhibitor p27Kip1 in growth inhibition of endometrium in the secretory phase and of hyperplastic endometrium treated with progesterone. 978 52

G1 phase progression of mammalian cells is mainly controlled by the cyclin-cyclin-dependent kinase (CDK)-CDK inhibitor-retinoblastoma protein (pRb) regulatory pathway. Cell cycle regulators controlling G1 phase progression are frequently involved in the carcinogenesis of many human cancer types. In hepatocellular carcinoma (HCC) the CDK inhibitor p16INK4 is predominantly inactivated by post-transcriptional regulation and p16INK4 inactivation participates in the early-stage of hepatocarcinogenesis and in disease progression. Reduced p21(WAF1/CIP1) expression, which is associated mainly with p53 gene mutation in HCCs, contributes to hepatocarcinogenesis. Reduced p27Kip1 expression is also frequently involved in HCC. The CDK inhibitors p16INK4, p21(WAF1/CIP1) and p27Kip1 are independently affected and a change in the expression of one or more of these inhibitors contributes to carcinogenesis of the majority (nearly 90%) of HCCs. Cyclin D1 amplification and overexpression play a role in the carcinogenesis of a subset (11-13%) of HCCs. Disruption of the regulatory system controlling G1 phase progression is a common event in human hepatocarcinogenesis. Further studies systematically analyzing the major regulators controlling G1 phase progression in a large cohort of HCCs will strengthen our understanding of the molecular mechanism underlying human hepatocarcinogenesis. Correcting alterations that have occurred in the G1 phase regulatory machinery may provide a novel weapon to treat and prevent HCC.
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PMID:Cell cycle regulators and human hepatocarcinogenesis. 984 Jan 20


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