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)

To test the hypothesis that steroid receptor-expressing cells are derived from the proliferative population, we examined expression of the p27(KIP1) inhibitor of cyclin-dependent kinase activity (a differentiation marker) while tracking the fate of proliferating cells in normal human breast tissue implanted into athymic nude mice using tritiated thymidine [3H]-dT. We identified a small number of cells that appeared to have divided just once before switching on p27(KIP1) expression. p27(KIP1)+ve cells also expressed steroid receptors, but not the Ki67 proliferation-associated antigen. These data support the hypothesis that steroid receptor-expressing cells are a differentiated population within the normal human breast epithelium.
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PMID:P27(KIP1) expression indicates that steroid receptor-positive cells are a non-proliferating, differentiated subpopulation of the normal human breast epithelium. 1105 5

Genistein, a naturally occurring isoflavone found chiefly in soy products, reportedly has antiprostate cancer effects, but the mechanisms underlying these effects are unknown. We studied the antiproliferative and apoptosis-inducing effects of genistein in the androgen-sensitive human prostate cancer cell line LNCaP. Viable cell number was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay; cell-cycle progression and apoptosis were evaluated by flow cytometry; apoptosis was also assessed by a histone enzyme-linked immunosorbent assay; and the expression of several cell-cycle- and apoptosis-related genes and their gene products was determined by northern blot analysis, western blot analysis, and/or assays based on polymerase chain reaction. Physiologic concentrations of genistein (< or = 20 microM) decreased LNCaP viable cell number in a dose-dependent manner, induced a G(1) cell-cycle block, decreased prostate-specific antigen mRNA expression, and increased p27(KIP1) and p21(WAF1) (mRNA and protein) but had no effect on apoptosis or the mRNA expression of the apoptosis- and cell-cycle-related markers bcl-2, bax, Rb, and proliferating cell nuclear antigen. Higher concentrations of genistein (> 20 microM) did induce apoptosis. We conclude that genistein (at physiologic concentrations) exerts potent antiproliferative effects on LNCaP cells by inducing a G(1) cell-cycle block. The antiproliferative effects of genistein may be mediated by increased levels of p27(KIP1) and p21(WAF1), which are negative cell-cycle regulators that act as cyclin-dependent kinase inhibitors and that have been recently linked with prostate carcinogenesis. These findings may provide insights into the mechanisms underlying the apparent antiprostate cancer effects of soy consumption observed in epidemiologic studies.
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PMID:Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. 1107 6

The present study was designed to determine the spatial correlation among extent of DNA synthetic activity, expressions of G(1)/S phase cyclins, cyclin-dependent kinases (CDKs) and CIP/KIP family of CDK inhibitors (CKIs), and activities of G(1)/S phase CDKs in glomeruli and outer medullae of kidneys during the active regeneration period after ischemic injury. DNA synthetic activity was measured using [(3)H]-thymidine autoradiogram in the kidney sections. Cyclin, CDK, and CKI proteins were determined by Western blot analysis. CDK activities were determined by phosphorylation amount using specific substrate. The protein levels of cyclins (D1, D3, E, A) and activities of CDK4 and CDK2 were increased concomitant with the induction of DNA synthetic activity in outer medullae, but not in glomeruli, in adult kidneys during DNA synthetic period after ischemic injury. The p27(KIP1) protein, but not the p21(CIP1) protein, increased equally in total kidney, glomeruli, and outer medullae after ischemic injury. These results indicate that renal tubules have an active cyclin/CDK system, while glomeruli, do not have a cyclin/CDK system during active regeneration of kidneys after ischemic injury.
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PMID:Differential changes of CDK activities in glomeruli and tubules during the active DNA synthetic period after ischemic injury. 1109 88

Osteoclasts, bone-resorbing multinucleated cells, develop from monocyte-macrophage lineage cells in the presence of osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) and macrophage colony-stimulating factor (M-CSF). M-CSF-dependent bone marrow macrophages (M-BMMPhis) from mouse bone marrow cells have been shown to differentiate into osteoclast-like multinucleated cells (OCLs) in the presence of soluble ODF/RANKL (sODF/RANKL) and M-CSF within 3 days. In this study, we found that stimulation of M-BMMPhis with sODF/RANKL induced a transient expression of cyclin-dependent kinase inhibitors (CDK inhibitors) p21(WAF1/CIP1) and p27(KIP1) by 24 h. The CDK inhibitor proteins disappeared by 48 h. Tumor necrosis factor alpha (TNF-alpha), which is reported to stimulate OCL differentiation, stimulated p21(WAF1/CIP1) and p27(KIP1) expression in M-BMMPhis as well. However, M-CSF alone did not stimulate the expression of the two CDK inhibitors. To clarify the role of p21(WAF1/CIP1) and p27(KIP1) in osteoclastogenesis, accumulation of these CDK inhibitors was aborted by antisense oligonucleotides. Treatment with p21(WAF1/CIP1) antisense oligonucleotide alone, or p27(KIP1) antisense oligonucleotide alone, showed a limited inhibitory effect on OCL formation. However, treatment with a mixture of these two antisense oligonucleotides strongly inhibited OCL formation. These results suggest that a combined modulation of the CDK inhibitors p21(WAF1/CIP1) and p27(KIP1) may be involved in osteoclast differentiation induced by ODF/RANKL.
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PMID:Osteoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). 1113 63

A previous study of ours unexpectedly found that in contrast to frequent reductions in non-small cell lung cancer, high expression of the p27(KIP1) cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), suggesting the possibility of high expression of nonfunctional p27(KIP1) in this virulent tumor. The study presented here, however, shows that p27(KIP1) in SCLC biochemically functions as a CDK inhibitor, clearly showing induction apparently associated with G(1)/G(0) arrest and efficient binding to and inhibition of the cyclin E-CDK2 complex. Interestingly, induction of p27(KIP1) seems to confer on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent experiments manipulating p27(KIP1) levels by using a sense p27(KIP1) expression construct or an antisense oligonucleotide supported this notion. These observations suggest that high expression of p27(KIP1) in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.
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PMID:Protective function of p27(KIP1) against apoptosis in small cell lung cancer cells in unfavorable microenvironments. 1114 82

Cell transplantation provides a way to compare the regulation of cell proliferation in the same cell type in cell culture and in a vascularized tissue structure in a host animal. The cyclin-dependent kinase inhibitors p57(KIP2), p21(WAF1/CIP1/SDI1) and p27(KIP1) have been extensively studied in cell culture but their role in growth control in tissues is less well understood. In the present experiments we compared the behavior of cell cycle inhibitors in human and bovine adrenocortical cells in culture and following cell transplantation in scid mice. p57 was expressed in the majority of cells in the intact human adrenal cortex. However, double immunofluorescence showed that cells that are in the cell cycle are p57(-) adrenocortical cells, p57 and p27 levels were not affected by inhibition of growth at high cell density, whereas p21 was higher in dividing than growth-inhibited cells. However, p21 was also high in senescent adrenocortical cells. After transplantation of human adrenocortical cells in scid mice, p57 and p27 were observed in most cells in the transplant tissue. Over time the number of p21(+) cells decreased greatly in human adrenocortical cells, but not in bovine adrenocortical cells. This difference correlated with lower levels of cell division (assessed by Ki-67 or incorporation of bromodeoxyuridine) in the human cells in transplant tissues in comparison to bovine cells. The differences between human and bovine cells were observed both when cells were transplanted beneath the kidney capsule and when cells were injected subcutaneously in collagen gel. We conclude that the behavior of p57, but not p21, is consistent with a role as a physiological mediator of proliferative quiescence in the adrenal cortex. The high level of p21 in dividing adrenocortical cells in culture, and in bovine adrenocortical cells in transplant tissues, may be a response to conflicting positive and negative growth influences. Cells may enter the cell cycle under the influence of a strong positive mitogenic signal, but coexisting negative growth stimuli trigger a p21-dependent block to further progression through the cell cycle. This model suggests that bovine adrenocortical cells respond to positive growth stimuli in transplant tissues but human cells lack this response.
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PMID:Contrasting roles of p57(KIP2) and p21(WAF1/CIP1/SDI1) in transplanted human and bovine adrenocortical cells. 1133 29

Calcium functions as a trigger for the switch between epithelial cell growth and differentiation. We report here that the calcium/calmodulin-dependent phosphatase calcineurin is involved in this process. Treatment of primary mouse keratinocytes with cyclosporin A, an inhibitor of calcineurin activity, suppresses the expression of terminal differentiation markers and of p21(WAF1/Cip1) and p27(KIP1), two cyclin-dependent kinase inhibitors that are usually induced with differentiation. In parallel with down-modulation of the endogenous genes, suppression of calcineurin function blocks induction of the promoters for the p21(WAF1/Cip1) and loricrin differentiation marker genes, whereas activity of these promoters is enhanced by calcineurin overexpression. The calcineurin- responsive region of the p21 promoter maps to a 78-bp Sp1/Sp3-binding sequence next to the TATA box, and calcineurin induces activity of the p21 promoter through Sp1/Sp3-dependent transcription. We find that the endogenous NFAT-1 and -2 transcription factors, major downstream targets of calcineurin, associate with Sp1 in keratinocytes in a calcineurin-dependent manner, and calcineurin up-regulates Sp1/Sp3-dependent transcription and p21 promoter activity in synergism with NFAT1/2. Thus, our study reveals an important role for calcineurin in control of keratinocyte differentiation and p21 expression, and points to a so-far-unsuspected interconnection among this phosphatase, NFATs, and Sp1/Sp3-dependent transcription.
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PMID:Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation. 1149 84

Galectin-3, a beta-galactoside-binding protein, is implicated in cell growth, adhesion, differentiation, and tumor progression by interactions with its ligands. Recent studies have revealed that galectin-3 suppresses apoptosis and anoikis that contribute to cell survival during metastatic cascades. Previously, it has been shown that human galectin-3 undergoes post-translational signaling modification of Ser(6) phosphorylation that acts as an "on/off" switch for its sugar-binding capability. We questioned whether galectin-3 phosphorylation is required for its anti-apoptotic function. Serine to alanine (S6A) and serine to glutamic acid (S6E) mutations were produced at the casein kinase I phosphorylation site in galectin-3. The cDNAs were transfected into a breast carcinoma cell line BT-549 that innately expresses no galectin-3. Metabolic labeling revealed that only wild type galectin-3 undergoes phosphorylation in vivo. Expression of Ser(6) mutants of galectin-3 failed to protect cells from cisplatin-induced cell death and poly(ADP-ribose) polymerase from degradation when compared with wild type galectin-3. The non-phosphorylated galectin-3 mutants failed to protect cells from anoikis with G(1) arrest when cells were cultured in suspension. In response to a loss of cell-substrate interactions, only cells expressing wild type galectin-3 down-regulated cyclin A expression and up-regulated cyclin D(1) and cyclin-dependent kinase inhibitors, i.e. p21(WAF1/CIP1) and p27(KIP1) expression levels. These results demonstrate that galectin-3 phosphorylation regulates its anti-apoptotic signaling activity.
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PMID:Galectin-3 phosphorylation is required for its anti-apoptotic function and cell cycle arrest. 1172 77

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

A human oral tumour progression model was established that consists of normal epithelial cells and three cell lines representing stages from dysplastic to metastatic cells. To investigate the impact of exogenous transforming growth factor-beta 1 on this model system, we analysed the responsiveness of those cells to transforming growth factor-beta 1 and explored the potential mechanism underlying the transforming growth factor-beta 1 activity. We found that the growth of all cell types, regardless of their stage of tumour progression, is inhibited by transforming growth factor-beta 1, although to different degrees. Transforming growth factor-beta 1 induced the expression of cyclin-dependent kinase inhibitors p15(INK4B), p21WAF1/(CIP1) and p27(KIP1). In contrast, transforming growth factor-beta 1 was found to stimulate the invasive potential of one cell type that represents the most advanced stage of tumour phenotype, suggesting that the impact of transforming growth factor-beta 1 on functional features of tumour cells other than cellular proliferation may play a significant role in the process of oral tumour progression.
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PMID:Transforming growth factor beta 1 dysregulation in a human oral carcinoma tumour progression model. 1202 54


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