Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The process of terminal differentiation is associated with exit from the cell cycle and loss of the proliferative potential of cells. The cyclin-dependent kinase inhibitors (CDIs) play critical roles in check-point functions during the cell cycle and as inhibitors of cell proliferation. Loss of their activities can impair development and differentiation and contribute to the uncontrolled proliferation characteristic of cancer cells. When the promyelocytic leukemia cell line HL60 is induced to differentiate in vitro, by a variety of agents, cellular levels of the CD1 proteins p21Cip1 and p27Kip1 are increased. To further address the roles of these two proteins in differentiation, we have overexpressed either a human p21Cip1 or p27Kip1 construct in HL60 cells. The overexpression of p21Cip1 accelerated both the monocytic and granulocytic differentiation of HL60 cells triggered by TPA or DMSO, respectively. The accelerated and more dramatic induction of differentiation seen in the p21Cip1 overexpressors was associated with a more rapid reduction of CDK2 kinase-associated activity, increased levels and more rapid dephosphorylation of the Rb protein, and increased levels of the cyclin D3 protein. Stable overexpression of p27Kip1 also enhanced TPA-induced differentiation of HL60 cells. These studies provide direct evidence that the increased expression of p21Cip1 and p27Kip1 play a causal role in the process of terminal differentiation of HL60 cells. Therefore, agents that enhance the expression of one or both of these proteins might be useful in therapy by enhancing the terminal differentiation of leukemia cells.
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PMID:Overexpression of p21Cip1 or p27Kip1 in the promyelocytic leukemia cell line HL60 accelerates its lineage-specific differentiation. 1069 93

Recent advances in the molecular biology has served to unveil the underlying genetic and epigenetic alterations in pituitary adenomas. Three nuclear transcriptional factors, AP-1, CREB, and Pit-1, which are targets of protein kinase C and A, appear to play critical roles in both neoplastic growth and hormone secretion in hormone-producing adenomas. The alteration of G proteins such as Gs and Gi2 is a direct cause of the activation of such transcriptional factors. Autocrine growth factor/cytokine loops also contribute to the augmented signal transductions. Bromocriptine and somatostatin analogs have effects to lower cellular cAMP level through inhibitory G proteins, although the mechanism leading to cellular apoptosis is unknown. On the other hand, most non-functioning adenomas may not have PKC- or PKA-mediated oncogenic mechanisms. Although the loss of Rb and p27Kip1 genes has been demonstrated as a cause of murine pituitary adenomas, the role of tumor suppressor genes for human pituitary adenomas remains elusive. However, potential candidates for the suppressor genes are now emerging. The recently cloned multiple endocrine neoplasia type I gene is one example. Alterations of c-myc/bcl-2, and ras, although rare, appear to be an important cause of the process by which adenoma cells acquire aggressive phenotypes. Further studies on the links between abnormal signal transductions and aberrant tumor suppressor genes will be needed to clarify the whole picture of pituitary oncogenesis.
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PMID:Molecular basis of pituitary oncogenesis. 1072 13

An accumulation of multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, cell adhesion molecules, and the growth factor/receptor system is involved in the course of multistep conversion of normal epithelial cells to clinical gastric cancer. Some of them differ depending on the histological type, well-differentiated (intestinal) and poorly differentiated (diffuse) types, suggesting the presence of two distinct genetic pathways. Genetic instability, chromosomal instability (telomere reduction), and immortality (activation of telomerase and expression of telomerase reverse transcriptase: TERT) participate in the initial step of stomach carcinogenesis. Because TERT protein expression precedes the telomerase activities in precancerous lesions, TERT expression may be a prerequisite for telomerase activation. The cyclin E gene is amplified in 15%-20% of gastric cancer. Reduced expression of a cyclin-dependent kinase (CDK) inhibitor, p27Kip1, is frequently found in gastric cancer associated with high grade malignancy. E2F-1, an important downstream target of cyclins/CDKs, is overexpressed in about 40% of gastric carcinomas, whereas gene amplification of E2F-1 rarely occurs. Loss of heterozygosity (LOH) of p73, the p53-related new tumor suppressor gene, preferentially occurs in well-differentiated adenocarcinomas of foveolar type expressing pS2, a gastric-specific trefoil factor, indicating the importance of p73 LOH in the genesis.
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PMID:Genetic and epigenetic alterations in multistep carcinogenesis of the stomach. 1077 29

The Akt/PKB protein kinase is implicated in the control of cell cycle progression and the suppression of apoptosis in cancer cells. Here we describe the use of a conditionally active form of Akt/PKB (M+ Akt:ER*) to study the ability of this protein to influence biological processes that are central to the process of oncogenic transformation of mammalian cells. Activation of M+ Akt:ER* in Rat1 cells elicited alterations in cell morphology and promoted anchorage-independent growth in agarose with high efficiency. Consistent with these observations, activation of M+ Akt:ER* suppressed the apoptosis of Rat1 cells that occurs after the detachment of these cells from extracellular matrix. Furthermore, activation of M+ Akt:ER* was sufficient to promote the progression of quiescent Rat1 cells into the S and G2-M phases of the cell cycle. In accord with this is the observation that activation of M+ Akt:ER* led to decreased expression of the cyclin-dependent kinase inhibitor p27Kip1 with a concomitant increase in cyclin-dependent kinase-2 activity. Perhaps surprisingly, activation of M+ Akt:ER* or expression of a constitutively active form of Akt led to rapid activation of MAP/ERK Kinase (MEK) and the extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinases in Rat1 cells. However, pharmacological inhibition of MEK by PD098059 did not inhibit the morphological alterations of Rat1 cells that occur after M+ Akt:ER* activation. These data suggest that M+ Akt:ER* can activate a number of pathways in Rat1 cells, leading to significant alterations in a number of biological processes. The conditional transformation system described here will allow further elucidation of the ability of Akt to contribute to both the normal response of cells to mitogenic stimulation and the aberrant proliferation observed in cancer cells.
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PMID:Oncogenic transformation of cells by a conditionally active form of the protein kinase Akt/PKB. 1091 95

Cellular and molecular evidence suggests that senescence is a powerful tumor-suppressor mechanism that prevents most higher eukaryotic cells from dividing indefinitely in vivo. Recent work has demonstrated that alpha-melanocyte stimulating hormone (alpha-MSH) or cholera toxin (CT) can activate a cAMP pathway that elicits proliferative arrest and senescence in normal human pigmented melanocytes. In these cells, senescence is associated with increased binding of p16INK4a to CDK4 and loss of E2F-binding activity. Because senescence may provide defense against malignant transformation of melanocytes, and because pigmentation is a strong defense against melanoma, we examined the ability of melanocytes derived from light and dark skin to respond to CT. Here we demonstrate that in melanocytes derived from dark-skinned individuals, CT-induced melanogenesis is associated with accumulation of the tumor suppressor p16INK4a, underphosphorylated retinoblastoma protein (pRb), downregulation of cyclin E, decreased expression of E2F1, and loss of E2F-regulated S-phase gene expression. In contrast to other senescent cell types, melanocytes have reduced or absent levels of the cyclin-dependent kinase inhibitors p27Kip1 and p21Waf-1. Importantly, melanocytes derived from light-skinned individuals accumulated smaller amounts of melanin than did those from dark-skinned individuals under the same conditions, and they continued to proliferate for several more division cycles. This delayed senescence may result from reduced association of p16 with CDK4, reduced levels of underphosphorylated pRb, and steady levels of cyclin E and E2F1. Because cyclin E-CDK2 inhibition is required for p16-mediated growth suppression, upregulation of p16 and downregulation of cyclin E appear essential for maintenance of terminal growth and senescence. Given the rising incidence of melanoma, identification of major growth regulatory proteins involved in senescence should shed light on the biology of this genetically mysterious tumor.
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PMID:Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/pRB and E2F1. 1091 49

p21Waf1 is a downstream effector of p53 and belongs to the Cip1/Kip1 family of cyclin-dependent kinase inhibitors. Thus, it is a potential tumor suppressor gene and likely plays an important role in tumor development. Moreover, reduced expression of p21Waf1 has been reported to have prognostic value in several human malignancies. In this study, we evaluated the prognostic value of p21Waf1 in bladder cancer compared with other clinicopathological features and with p27Kip1 and p53 expression. A total of 96 superficial (pTa-1) human bladder carcinomas were immunohistochemically stained for p21Waf1 protein expression. Positive p21Waf1 staining (> or =5% positive nuclei) was observed in 68 of the 96 (71%) tumors. p21Waf1 expression was neither associated with tumor stage (P = 0.9) nor with tumor grade (P = 0.18) but was significantly associated with both p53 protein expression (> or =20% positive nuclei; P = 0.007) and with p53 gene mutations (P = 0.017). A significant correlation was also observed between positivity for p21Waf1 and high (>50% positive cells) p27Kip1 expression (P = 0.04). With regard to prognosis, patients whose tumors showed absence of p21Waf1 staining displayed a significantly shorter overall survival (P = 0.01 by log-rank test). However, p21Waf1 expression did not correlate with disease-free survival (P = 0.15 by log-rank test). On a multivariate analysis that also included p53 and p27Kip1 expression, negative p21Waf1 staining was an independent predictor of reduced overall survival (P = 0.004; relative risk, 5.32), stronger than age and tumor stage. These data indicate that expression of p21Waf1 protein strongly correlates with survival and might represent a useful prognostic marker in primary superficial bladder carcinomas.
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PMID:Loss of p21Waf1 expression is a strong predictor of reduced survival in primary superficial bladder cancers. 1095 94

Cancer cells are known to display up-regulation of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), the key enzymes in the biosynthesis of polyamines that are essential for cellular proliferation. We have shown previously that overexpression of ODC or AdoMetDC alone can induce tumorigenic transformation of rodent fibroblasts. Because the subversion of normal cell cycle control is thought to be a crucial event in cancer development, we examined ODC- and AdoMetDC-transformed fibroblasts for alterations in the cell cycle components. The level of cyclin D1 and cyclin D1-dependent kinase and total cyclin-dependent kinase (CDK) 4 activities were elevated in the ODC transformants and particularly in the AdoMetDC transformants. Cyclin E content was not elevated, but a moderate increase in cyclin E-dependent kinase activity was seen in both cells. Total CDK2 activity was increased only in the ODC-transformed cells. The amount of the p27Kip1 CDK inhibitor was greatly decreased in both transformants. Nevertheless, p27Kip1 was present in the active cyclin D1/CDK4 complexes in the cells but absent from the cyclin E/CDK2 complexes. Restoration of p27Kip1 expression in the ODC- and AdoMetDC-transformed cells by transfection resulted in growth inhibition, but not in morphological reversion. An elevation in the level of hyperphosphorylated retinoblastoma protein was observed mainly in the ODC-transformed cells. These results suggest that the expression of ODC or AdoMetDC may affect cell cycle regulation in many ways. However, the largest common effect, which is therefore potentially relevant to some aspects of transformation, appears to be the constitutive down-regulation of p27Kip1 and its loss from the cyclin/CDK2 complexes.
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PMID:Loss of p27Kip1 from cyclin E/cyclin-dependent kinase (CDK) 2 but not from cyclin D1/CDK4 complexes in cells transformed by polyamine biosynthetic enzymes. 1101 54

In the present study, we examine whether human pancreatic carcinoma cells express peroxisome proliferator-activated receptor gamma (PPARgamma) and the effect of PPARgamma activation by its selective ligand on cellular growth in pancreatic cancer cells. Immunohistochemical study of resected human pancreata using a polyclonal PPARgamma antibody revealed that PPARgamma protein expression in the nuclei of carcinoma cells was observed in 9 of 10 pancreatic adenocarcinomas. In contrast, normal pancreatic duct epithelial cells in the samples expressed no PPARgamma. Reverse transcription-PCR and Northern blot analysis demonstrated that all four tested human pancreatic cancer cell lines, PK-1, PK-8, PK-9, and MIA Paca-2, expressed PPARgamma mRNA. Luciferase assay in PK-1 cells showed that troglitazone, a selective ligand for PPARgamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose-dependent fashion. Troglitazone inhibited the growth of all four pancreatic carcinoma cell lines in a dose-dependent manner. Cell cycle analysis by flow cytometry demonstrated that troglitazone induced G1 arrest in PK-1 cells. To examine the role of cyclin-dependent kinase inhibitors in the G1 arrest by troglitazone, we determined p27KiP1, p21CiP1/Waf1, or p18Ink4c protein expression by Western blot analysis in troglitazone-treated PK-1 cells. Troglitazone increased p27Kip1 but not p21Cip1/Waf1 or p18Inkc protein levels in time- and dose-dependent manners. To clarify the functional importance of p27Kip1 in the cell growth inhibition by troglitazone. All these results suggest that PPARgamma could be considered as a possible target molecule for treatment in human pancreatic carcinomas.
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PMID:Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human. Pancreatic carcinoma cells. 1103 3

Previous studies by our laboratory have shown that a noncalcemic fluorinated analog of 1alpha,25-dihydroxyvitamin D3, 1alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholcal ciferol (F6-D3), significantly reduced the frequency of colonic adenomas and completely abolished the development of colonic adenocarcinomas in rats treated with azoxymethane. The mechanisms involved in this analog's chemopreventive actions, however, remain unclear. In the present study, we now show that although both 1alpha,25-dihydroxyvitamin D3 and F6-D3 inhibited the proliferation of CaCo-2 cells, a human colonic adenocarcinoma cell line, by increasing their doubling times, only F6-D3 caused an arrest of these cells in the G1 phase of their cell cycle. This arrest was accompanied by an increase in the expression of the cyclin-dependent kinase (cdk) inhibitor proteins, p2Waf1 and p27Kip1, which served to decrease the activity of cyclin-dependent kinase 2 and cyclin-dependent kinase 6, whereas the expression and phosphorylation of pRB were unchanged. In contrast to the increased expression of these cdk inhibitors, the expression of cyclin E was decreased, which further inhibited the activity of cyclin-dependent kinase 2. Collectively, the inhibition of these cyclin-dependent kinases served to arrest the CaCo-2 cells, independent of changes in pRB. Furthermore, antibody neutralization studies suggest that transforming growth factor-beta may mediate the coassociations between cdk2 and p27Kip1 and cyclin E induced by F6-D3. These data indicate that cell cycle arrest may, at least in part, underlie the chemopreventive actions of F6-D3 observed in the azoxymethane model of colon cancer. Furthermore, if the antiproliferative action observed in CaCo-2 cells also occurs in human colonic epithelium, F6-D3 may have chemopreventive potential against human colon cancer, as well.
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PMID:A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: roles of cyclin E, p21Waf1, and p27Kip1. 1108 22

The cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2 are thought to regulate progression of the cell cycle. We have previously shown that the phenotypes of p27-/- mice are substantially different from those of p57-/- mice, suggesting that spatial and temporal expression patterns of p27Kip1 and p57Kip2 might be distinct. In this study, the roles of p27Kip1 and p57Kip2 in development were examined by characterizing their expression patterns during mouse embryogenesis by immunohistochemical analysis. Whereas certain organs and tissues (brain, lens, ganglion, lung, heart, liver, skin and kidney) expressed both proteins, others expressed only p27Kip1 (thymus, spleen, retina, testis and ovary) or only p57Kip2 (gut, palate, pancreas, cartilage and skeletal muscle). In addition, some organs expressed both p27Kip1 and p57Kip2 but showed mutually exclusive patterns of distribution among tissues. Thus, in the adrenal gland, p57Kip2 was expressed in the cortex but not in the medulla, whereas p27Kip1 was expressed in the medulla but not in the cortex. Whereas the expression of p57Kip2 in most tissues was restricted to embryogenesis, expression of p27Kip1 in many tissues was maintained in adult animals. Double-label immunofluorescence staining with either anti-p27Kip1 or anti-p57Kip2 and anti-BrdU revealed that the expression of p27Kip1 and p57Kip2 was inversely correlated with cell proliferation, suggesting that p27Kip1 and p57Kip2 are expressed exclusively in postmitotic cells. These complex spatial and temporal patterns of expression are consistent with the phenotypes of mice deficient in p27Kip1 or p57Kip2, and they suggest that these proteins might play important roles in tissue development.
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PMID:Spatial and temporal expression patterns of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2 during mouse development. 1121 61


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