Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclin-dependent kinase 4 (cdk4) inhibitor (p16INK4/MTS1/CDKN2) gene has been recently identified as a putative tumor suppressor gene because of the high frequency of homozygous deletion observed in numerous human tumor cell lines, including leukemias. However, results obtained from uncultured tumor samples have led to discussion of the relevance of these findings. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blot analysis, we have investigated p16INK4A gene at both RNA and genomic levels in various types of leukemias: acute myeloid leukemia (AML) (n = 23); acute lymphocytic leukemia (ALL) (n = 22) and B cell chronic lymphoproliferative disorders (CLPD) (n = 33). p16INK4A mRNA expression was not found in only 1/20 AML and 2/23 CLPD samples. Conversely, p16INK4A mRNA was not detected in 5/17 ALL cases, and intensity of PCR products were barely detectable in seven additional cases, possibly related to the contamination by normal cells in some cases. By Southern blotting, a homozygous deletion of p16INK4A gene was found in 6/17 ALL cases (35%) among which 4/6 were negative or weakly positive by RT-PCR assay. None of the five AML and 20 CLL samples studied had p16INK4A deletion. Sequence analysis of p16INK4A exon 2 did not show point mutation in two of these cases lacking mRNA expression. Our data provide further evidence that among hematological malignancies, ALL are the most likely to be associated with p16INK4A inactivation, mainly by homozygous gene deletion. Since most hematological malignancies-except ALL-are infrequently associated with p16INK4A and retinoblastoma (Rb) gene alteration it seems worthwhile to explore cdk4 and cdk6 expression to determine whether or not the disruption of the p16INK4A/Rb/cdk4/cdk6 regulatory loop might play a role in their pathogenesis.
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PMID:Alterations of cyclin-dependent kinase 4 inhibitor (p16INK4A/MTS1) gene structure and expression in acute lymphoblastic leukemias. 763 Jan 99

Rearrangement and overexpression of the PRAD1/cyclin D1 oncogene, a cell cycle regulator, have been implicated in the pathogenesis of a subset of parathyroid adenomas. Recently, two cell cycle regulators that inhibit the cyclin D1-associated kinases cdk4 and cdk6 have been identified: p16 and p15, the products of the INK4A (also known as CDKN2, MTS1) and INK4B (also known as MTS2) putative tumor suppressor genes located on 9p21. Because inactivation of the p16 or p15 genes might be expected to result in oncogenic consequences similar to those from cyclin D1 overexpression, we examined 25 parathyroid adenomas for 1) allelic loss of polymorphic DNA loci on chromosome arm 9p, 2) homozygous deletions of the p16 and p15 genes by Southern blot analysis, and 3) mutations of the p16 and p15 genes by single strand conformational polymorphism analysis. Heterozygous allelic loss at 9p was observed in 4 of 25 adenomas (16%); their smallest shared region of deletion was 9p21-pter, which includes both the p16 and p15 genes. However, single strand conformational polymorphism analysis of all 3 exons of the p16 gene and both exons of the p15 gene failed to demonstrate mutation in any of the 25 cases, and homozygous deletions of the p16 and p15 genes, which are present in some human cancers, were not found in any parathyroid tumors. These observations indicate that inactivating mutations or homozygous deletions of the p16 and p15 genes occur uncommonly, if ever, in parathyroid adenomas; however, loss of a different tumor suppressor gene (or genes) on 9p appears to contribute to the pathogenesis of a significant percentage of these tumors.
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PMID:Loss of chromosome arm 9p DNA and analysis of the p16 and p15 cyclin-dependent kinase inhibitor genes in human parathyroid adenomas. 885 19

p27(Kip1) (p27) is a member of the universal cyclin-dependent kinase inhibitor (CDKI) family and a putative tumor suppressor gene. In several tumors including lung cancer, decreased expression of p27 is associated with poor prognosis. These observations suggest a potential role for p27 as a new gene therapy target. In this study, we constructed adenovirus expressing human p27 (ad-p27) and investigated its antitumor effects on human lung cancer cell lines. Upon transduction of several human lung cancer cells with ad-p27, a high level of p27 expression, with a decrease in cdk2 and an increase in cyclin E were observed. These changes resulted in G1/S arrest. Transduction of human lung cancer cell lines with ad-p27 showed in vitro growth inhibition and a marked suppression of colony formation upon soft agar clonogenic assay. Direct intratumoral injection of ad-p27 induced the growth suppression of established lung tumors in nude mice. From these observations, gene therapy using ad-p27 seems to offer a potential basis for the development of new cancer gene therapy modality and a useful tool to investigate the mechanisms of cell cycle control.
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PMID:Adenovirus expressing p27(Kip1) induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts. 1116 93

Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20-25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.
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PMID:Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. 1184 Feb 72

Although mutations in the parkin gene are frequently associated with familial Parkinsonism, emerging evidence suggests that parkin also plays a role in cancers as a putative tumor suppressor. Supporting this, we show here that parkin expression is dramatically reduced in several breast cancer-derived cell lines as well as in primary breast cancer tissues. Importantly, we found that ectopic parkin expression in parkin-deficient breast cancer cells mitigates their proliferation rate both in vitro and in vivo, as well as reduces the capacity of these cells to migrate. Cell cycle analysis revealed the arrestment of a significant percentage of parkin-expressing breast cancer cells at the G1-phase. However, we did not observe significant changes in the levels of the G1-associated cyclin D1 and E. On the other hand, the level of cyclin-dependent kinase 6 (CDK6) is dramatically and selectively elevated in parkin-expressing breast cancer cells, the extent of which correlates well with the expression of parkin. Interestingly, a recent study demonstrated that CDK6 restrains the proliferation of breast cancer cells. Taken together, our results support a negative role for parkin in tumorigenesis and provide a potential mechanism by which parkin exerts its suppressing effects on breast cancer cell proliferation.
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PMID:Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells. 2063 Aug 68

The growth suppressing activity of the retinoblastoma susceptibility gene product, pRb, is down regulated by cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) whose activity is negatively regulated by CDK inhibitors of the p16 family. We have previously reported point mutations of the p16/CDKN2 gene in 4 (57%) of 7 oral squamous cell carcinoma (SCC) cell lines. In the current study, we examined the mutational status of CDK inhibitors, including 3 genes of the p16 family (p16, p15 and p18), in 50 human oral SCCs, and also additional results concerning their loss of heterozygosity in the regions of the p16, p15 and p18 genes. Our results demonstrated that 2 of 50 (4%) primary oral SCCs had nonsense mutations of the p16 gene, and 2 of 50 (4%) showed frameshift mutations of the p18 gene. However, we detected no mutation of the p15 gene in any of the 50 oral SCCs. In addition, no evidence of hypermethylation of the p16 gene was found in our series. To better understand the extent of alterations affecting chromosomes 9p21 (location of the p15/p16 genes) and 1p32 (location of the p18 gene), loss of heterozysity (LOH) on these locations was examined. LOH was detected in 16 of 34 (47%) informative samples that had no detectable mutation of the p15/p16 genes on 9p21, but we found no LOH at 1p32. These results strongly suggest that a putative tumor suppressor gene for oral SCC may be present on chromosome 9p21-22, while the p16, p15 and p18 genes play a minor role in the oncogenesis of this cancer.
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PMID:Rare mutations of the growth suppressor genes involved in negative regulation of the cell cycle. 2152 14

Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also p53-dependent. Because miRNA-16 is a putative tumor suppressor miRNA, and others have found that miRNA-16 suppresses proliferation, we hypothesized that the p53-dependent G1 arrest associated with PAD inhibition was, in turn, dependent on miRNA-16 expression. Results are consistent with this hypothesis. As well, we found the G1 arrest is at least in part due to the ability of Cl-amidine-mediated expression of miRNA-16 to suppress its' G1-associated targets: cyclins D1, D2, D3, E1, and cdk6. Our study sheds light into the mechanisms by which PAD inhibition can protect against or treat colon cancer.
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PMID:The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest. 2330 84