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 secreted proteoglycan decorin has been implicated in the negative control of cell proliferation primarily by virtue of its ability to block transforming growth factor-beta. Moreover, decorin expression is markedly up-regulated during quiescence but suppressed upon viral transformation, whereas de novo decorin expression in colon carcinoma cells abrogates the malignant phenotype by arresting the cells in the G1 phase of the cell cycle. Here we show that this decorin-induced growth arrest is associated with up-regulation of p21 mRNA and protein in a transforming growth factor-beta- and p53-independent pathway. The augmented p21 protein is present as a multimeric complex with various cyclins and cyclin-dependent kinases in the nuclei of decorin-expressing cells, thereby leading to suppression of cyclin-dependent kinase activity and block of cell division. Through the usage of decorin-specific antisense oligodeoxynucleotide treatment, we demonstrate that the expression of decorin is closely linked to that of p21 and that abrogation of decorin leads to suppression of p21 and restoration of cell division. Collectively, our results provide a plausible mechanism by which decorin may contribute to retard and suppress the growth of tumor cells in vivo.
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PMID:Decorin-induced growth suppression is associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases. 870 60

Cellular aging is accompanied by a reduction in proliferative activity and changes in gene expression. To further elucidate the mRNA phenotype of aging fibroblasts we have monitored the expression of an array of genes implicated in regulating cell-cycle progression. Fourteen genes, including 3 cyclin-dependent kinase (CDK) inhibitors (p16INK4, p21SDI/CIP/WAF and p27KIP), 5 cyclins, 4 CDKs, Cdi-1, and PCNA were tested in four primary fibroblast strains. Relative mRNA expression levels were assessed using a rapid and sensitive Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) assay called the "Primer-dropping" method. p16INK4, a specific inhibitor of the cyclin D-associated kinases CDK4 and CDK6, was, in addition to p21 and cyclin D1, overexpressed in higher passage cells, while the abundance of the D-type kinase mRNAs remained relatively constant. Levels of cyclin H, a component of the CDK-activating kinase (CAK) were markedly reduced in all strains examined, suggesting that the activity of target cyclin/CDK complexes may not be activated in aging cells. These results corroborate and extend previous observations demonstrating elevated expression of specific cell cycle genes in higher passage cells and suggest that overexpression of the CDK-inhibitors p16INK4 and p21SDI/CIP/WAF, but not p27KIP, may contribute to lower proliferative activity of senescing primary fibroblasts.
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PMID:Differential CDK-inhibitor gene expression in aging human diploid fibroblasts. 870 1

Considerable progress has been made toward elucidating the pathway of induction of terminal differentiation of transformed cells by hybrid polar compounds such as hexamethylene bisacetamide (HMBA). HMBA alters factors controlling G1-to-S phase transition, leading to G1 arrest and inhibition of DNA synthesis. Among the inducer-mediated changes, suppression of cyclin-dependent kinase cdk4, which may be required for phosphorylation of the retinoblastoma protein pRB and perhaps p107, is critical in the pathway of terminal differentiation. HMBA induces an increase in the level of p21 which inhibits cyclin-dependent kinase activity and, in turn, may cause cells to arrest in G1. p107 complexes with transcription factor E2F, which may alter E2F-dependent gene transcription. the relationship of the inducer-mediated changes in cyclins, cdks, cyclin-cdk inhibitors and transcription factors to the expression of differentiation-specific genes has not yet been established. The hybrid polar compounds are potent inducers of differentiation of a wide variety of transformed cells. HMBA has been shown to induce differentiation of neoplastic cells in patients. A second generation of hybrid polar compounds have been synthesized which are up to 1000 fold more potent than HMBA on a molar basis as inducers of murine erythroleukemia (MEL) cells and other transformed cells in vitro. The potential of these compounds as clinically useful inducers of differentiation of cancer cells is under study.
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PMID:Cell cycle regulatory proteins are targets for induced differentiation of transformed cells: Molecular and clinical studies employing hybrid polar compounds. 871 72

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents, and its overexpression causes arrest in the G1 phase of the cell cycle by a mechanism dependent on the tumour-suppressor protein p53 (refs 2-4). Here we investigate the possible role of c-Abl in growth arrest induced by DNA damage. Transient transfection experiments using wild-type or inactivated c-Abl show that both induce expression of p21, an effector of p53, but only wild-type c-Abl downregulates the activity of the cyclin-dependent kinase Cdk2 and causes growth arrest. Exposure to ionizing radiation of cells that stably express active or inactive c-Abl is associated with induction of c-Abl/p53 complexes and p21 expression. However, cells expressing the dominant-negative c-Abl mutant and cells lacking the c-abl gene are impaired in their ability to downregulate Cdk2 or undergo G1 arrest in response to ionizing radiation. We also show that expression of c-Abl kinase in p21(-1-), but not in p53(-1-), cells results in downregulation of Cdk2. Our results suggest that c-Abl kinase contributes to the regulation of growth arrest induced by ionizing radiation by a p53-dependent, p21-independent mechanism.
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PMID:Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. 871 45

Arterial injury induces a series of proliferative, vasoactive, and inflammatory responses that lead to vascular proliferative diseases, including atherosclerosis and restenosis. Although several factors have been defined which stimulate this process in vivo, the role of specific cellular gene products in limiting this response is not well understood. The p21 cyclin-dependent kinase inhibitor affects cell cycle progression, senescence, and differentiation in transformed cells, but its expression in injured blood vessels has not been investigated. In this study, we report that p21 protein is induced in porcine arteries following balloon catheter injury and suggest that p21 is likely to play a role in limiting arterial cell proliferation in vivo. Vascular endothelial and smooth muscle cell growth was arrested through the ability of p21 to inhibit progression through the G1 phase of the cell cycle. Following injury to porcine arteries, p21 gene product was detected in the neointima and correlated inversely with the location and kinetics of intimal cell proliferation. Direct gene transfer of p21 using an adenoviral vector into balloon injured porcine arteries inhibited the development of intimal hyperplasia. Taken together, these findings suggest that p21, and possibly related cyclin-dependent kinase inhibitors, may normally regulate cellular proliferation following arterial injury, and strategies to increase its expression may prove therapeutically beneficial in vascular diseases.
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PMID:Role of the p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury. 875 75

The cyclin-dependent kinase (Cdk) inhibitor p21 is induced by the tumor suppressor p53 and is required for the G1-S block in cells with DNA damage. We report that there are two copies of a cyclin-binding motif in p21, Cy1 and Cy2, which interact with the cyclins independently of Cdk2. The cyclin-binding motifs of p21 are required for optimum inhibition of cyclin-Cdk kinases in vitro and for growth suppression in vivo. Peptides containing only the Cy1 or Cy2 motif partially inhibit cyclin-Cdk kinase activity in vitro and DNA replication in Xenopus egg extracts. A monoclonal antibody which recognizes the Cy1 site of p21 specifically disrupts the association of p21 with cyclin E-Cdk2 and with cyclin D1-Cdk4 in cell extracts. Taken together, these observations suggest that the cyclin-binding motif of p21 is important for kinase inhibition and for formation of p21-cyclin-Cdk complexes in the cell. Finally, we show that the cyclin-Cdk complex is partially active if associated with only the cyclin-binding motif of p21, providing an explanation for how p21 is found associated with active cyclin-Cdk complexes in vivo. The Cy sequences may be general motifs used by Cdk inhibitors or substrates to interact with the cyclin in a cyclin-Cdk complex.
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PMID:Cyclin-binding motifs are essential for the function of p21CIP1. 875 24

Heat shock induces several events in cells including a series of gene expressions and cell cycle arrest. Recently, several types of cell cycle arrest have been related to the function of cyclin-dependent kinase inhibitors (CKI). Here we show that heat shock treatment up-regulates p21 CKI mRNA and protein in A172 glioma cells and arrests the cell cycle at the G1 phase, p53-deficient cell lines, MDAH041 and T98G, also showed a significant increase in p21 CKI expression after heat stress, indicating that the induction involves a p53-independent pathway. The kinetics of this transient induction, which is not affected by cycloheximide, demonstrate that p21 CKI is an immediate-early response gene.
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PMID:Heat shock-mediated cell cycle arrest is accompanied by induction of p21 CKI. 878 Jun 86

p21 Cip1 was first isolated as one of the cyclin-dependent kinase (Cdk) interacting proteins induced by wild-type p53 gene product, and it appears to play an essential regulatory role in the control of cell proliferation as a potent, tight-binding inhibitor of cyclin-Cdk complex that blocks the G1/S transition of the cell cycle. We have now examined the p21 Cip1 mRNA expression levels in 16 surgically excised human colorectal tumor and non-tumor tissues by Northern-blot analysis with reference to the identification of p53 gene mutations. p53 gene mutations were detected in 6 tumor tissues but not in the other 10 tissues by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method and following direct sequencing. The mean p21 Cip1 mRNA expression level in tumor tissues was significantly suppressed compared to that of non-tumor tissues, irrespective of p53 gene mutations. In p53 gene mutation-detected cases, the mean expression level of p21 Cip1 mRNAs of tumor tissues was about 60% of that of cases without p53 gene mutation. Moreover, the relative mRNA expression levels of p21 Cip1 significantly decreased as the pathohistological stages progressed by Dukes' staging system, while in patients with liver metastasis these levels were significantly suppressed compared to those of patients without organ metastasis. These results indicate that reduced expression of p21 Cip1 mRNA is critical for growth activity and malignant potential of human colorectal carcinoma, and that the decrease in p21 Cip1 mRNA level is due to p53 gene mutation as well as other mechanisms during human colorectal carcinogenesis.
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PMID:Reduced messenger RNA expression level of p21 CIP1 in human colorectal carcinoma tissues and its association with p53 gene mutation. 879 64

Deregulation of cyclin, cyclin-dependent kinases (CDKs) and their inhibitors could have a pivotal role in the development of diverse human cancers. We examined the genetic status and the expression of CDK inhibitors (p21, p27, p16 and p15), CDK2 and cyclins (A, D1 and E) in eight gastric carcinoma cell lines, in comparison with the status of p53 gene alterations. All the cell lines (except MKN-28) that contained a p53 gene abnormality expressed very low or undetectable levels of p21 mRNA, while the cell lines (MKN-45 and -74) with wild-type p53 gene expressed high levels of p21 mRNA. An inverse correlation was found between the level of p21 mRNA and the expression of mRNAs for CDK2 and G1 cyclins. MKN-28 was an exception; it contained mutated p53, and expressed mRNAs for p21, CDK2 and G1 cyclins at high levels. Only MKN-45 and -74, with wild-type p53, expressed considerable levels of p21 protein. Homozygous deletion of the p16 and p15 genes was detected in two (MKN-45 and HSC-39) of the eight gastric carcinoma cell lines, p16 protein was not expressed in three cell lines (MKN-28, MKN-74 and KATO-III), as well as MKN-45 and HSC-39. Rearrangement of the p15 gene was found in TMK-1. Rearrangement of the p27 gene was detected in MKN-45, although the expression of p27 protein was well preserved in all the gastric carcinoma cell lines. The expression of pRb was also preserved in all the cell lines except KATO-III. No obvious correlation was observed between the p53 gene status and the expression of p27 and p16. These findings suggest that abnormal regulation of CDK2/cyclins and CDK inhibitors might be involved in deregulated growth of gastric carcinomas.
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PMID:Genetic status and expression of the cyclin-dependent kinase inhibitors in human gastric carcinoma cell lines. 879 88

The alveolar surface of the lung is a major target for oxidant injury, and its repair following injury is dependent on the ability of its stem cells, the type 2 cells, to initiate proliferation. From previous studies it is likely that events located before the entry into the S phase of the cell cycle and involving several components of the insulin-like growth factor system as well as of transforming growth factor-beta (TGF-beta) play a key role in growth regulation of oxidant-exposed type 2 epithelial cells. To gain further insights into these mechanisms, we explored the effects of O2 exposure on G1 cyclins and their cyclin-dependent kinases (CDKs). We documented an increased expression of these genes in O2-treated type 2 cells. However, despite this induction, a dramatic decrease in cyclin E-CDK2 activity, but not in cyclin D-CDK4 activity, was found. The concomitant induction of CDK inhibitory proteins (CKIs), mainly p21(CIP1), suggests that accumulation of inactive cyclin E-CDK2 activity is due to CKI binding. We also provided evidence that the mechanisms regulating this process involved TGF-beta as anti-TGF-beta antibody treatment was able to reduce the oxidant-induced inhibition of cyclin E-CDK2 activity. Taken together, these results suggest that oxidants may block entry into S phase by acting on a subset of late G1 events whose alterations are sufficient to impair the activation of cyclin E-CDK2 complexes.
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PMID:Altered regulation of G1 cyclins in oxidant-induced growth arrest of lung alveolar epithelial cells. Accumulation of inactive cyclin E-DCK2 complexes. 881 Feb 66


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