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 p16 (CDKN2/cyclin-dependent kinase-4 inhibitor/multiple tumor suppressor-1) gene is frequently altered in cell lines and some types of cancers. To assess whether alterations of this gene are important in the pathogenesis of cervical cancer, we examined 41 primary tumors and 8 cell lines, using Southern blot and polymerase chain reaction-single strand conformation polymorphism analyses. We did not detect any deletions or mutations, which indicates that inactivation of the p16CDKN2 gene is not critical in the tumorigenesis of cervical cancer or in establishment of cervical cancer cell lines.
 ...
PMID:p16 (CDKN2/cyclin-dependent kinase-4 inhibitor/multiple tumor suppressor-1) gene is not altered in uterine cervical carcinomas or cell lines. 882 52

Transforming growth factor beta (TGF beta) inhibits cell proliferation by inducing a G1 cell-cycle arrest. Cyclin/CDK complexes have been implicated in this arrest, because TGF beta treatment leads to inhibition of cyclin/CDK activity. We have investigated the role of the retinoblastoma protein (pRb) in TGF beta-induced growth arrest by using RB+/+ and RB-/- primary mouse embryo fibroblasts. In both of these cell types, TGF beta inhibits CDK4-associated kinase activity. However, whereas CDK2-associated kinase activity was completely inhibited by TGF beta in the wild-type cells, it was reduced only slightly in the RB mutant cells. In addition, at high-cell density the growth-inhibitory effects of TGF beta are no longer observed in the RB-/- cells; on the contrary, TGF beta treatment promotes the growth of these mutant fibroblasts. Thus, under certain cellular growth conditions, elimination of pRb transforms the growth-inhibitory effects of TGF beta into growth-stimulatory effects. These observations could help to explain why TGF beta is often found to enhance tumorigenicity in vivo and why inactivation of the RB gene leads to tumorigenesis.
 ...
PMID:TGF beta-induced growth inhibition in primary fibroblasts requires the retinoblastoma protein. 888 30

An understanding of the biological significance of the multiple genetic alterations identified in clinical bladder cancers to the stepwise pathogenesis of the disease is evolving. Alterations in p53 and pRb, products of the chromosomes 17p13 TP53 and 13q14 RB tumor suppressor genes, occur in approximately 50% and approximately 33% of bladder cancers respectively, and are associated with later stage, higher grade disease. p53 and pRb alterations are also known to occur in early stage bladder carcinoma in situ where they are thought to represent a poor prognosis for tumor progression. Allelic loss of genes on 9p21 occurs in approximately 50% of bladder cancers, but whether the only critical gene in this region is the CDKN2/p16 cyclin/CDK inhibitor is at present uncertain. Amplification and/or overexpression of the oncogenes epidermal growth factor receptor and erbB2 are associated with later stage disease. Finally, recent findings generated using in vitro transformation systems with human uroepithelial cells provide strong evidence that loss of genes on 3p, which occurs in approximately 20% of bladder cancers, and/or gain of genes on 20q play an important role in blocking HUC cellular senescence. This latter phenotype should represent a critical step in oncogenesis, as cells that do not senesce can survive to accumulate the multiple genetic alterations associated with invasive and metastatic bladder cancers. Further understanding of the biochemical mechanisms underlying these genetic changes will provide the additional information needed to design better strategies for bladder cancer intervention and treatment.
 ...
PMID:A molecular genetic model of human bladder cancer pathogenesis. 889 68

The genes of murine cyclin D-dependent kinase inhibitors, p15INK4b and p16INK4a, are located in a region of chromosome 4 where overlapping deletions were found in lung adenocarcinomas. The p16INK4a gene uniquely consists of alternative first exons (E1alpha and E1beta), which are spliced to exon 2 in alternative reading frames to either encode p16INK4a (alpha form) or another potential tumor suppressor, p19ARF (beta form). We examined 99 lung adenocarcinomas of C3H/HeJ x A/J F1(C3AF1) and A/J x C3H/HeJ F1(AC3F1) mouse hybrids and 18 (13 metastatic, 5 nonmetastatic) tumorigenic mouse lung epithelial cell lines for p15INK4b and p16INK4a gene inactivation. Homozygous codeletion occurred in eight of the 13 (62%) metastatic, four of the five (80%) nonmetastatic cell lines, but in only six of 99 (6%) adenocarcinomas. Neither p15INK4b nor p16INK4a gene was individually deleted in any of the tumors or cell lines, and all deletions of the p16INK4a gene extended into exon 2, which would be expected to disrupt the functions of both p16INK4a and p19ARF. We also detected no intragenic mutations of either gene in 44 tumors that displayed loss of heterozygosity at the p16INK4a locus or in any of the cell lines. Transcript levels of p16INK4a-alpha, p16INK4a-beta and p15INK4b also were examined in each of the cell lines that retained copies of these genes. Whereas an immortal mouse lung epithelial cell line (E10) and two metastatic tumor cell lines (LM1 and E9) expressed p16INK4a-beta and p15INK4b mRNA, the alpha transcript of p16INK4a was detected in only the LM1 cell line. These results suggest that both p15INK4b and p16INK4a (alpha and beta) are targets of inactivation in mouse lung tumorigenesis.
 ...
PMID:Homozygous codeletion and differential decreased expression of p15INK4b, p16INK4a-alpha and p16INK4a-beta in mouse lung tumor cells. 893 34

Inhibitors of cyclin-dependent kinases provide a major mechanism of negative regulation on cell cycle progression. Defects in the function of the CDK inhibitors may lead to uncontrolled cell proliferation and potentially facilitate tumorigenesis. The p16INK4 family of CDK inhibitors specifically prevent the phosphorylation of the retinoblastoma susceptibility gene product, pRb, by inhibiting the kinase activity of CDK4 and CDK6, thereby keeping pRb in its active form as a growth suppressor. The loss of p16INK4 inhibitory activity would, therefore, have the same consequence as the loss of pRb growth suppressing activity. The p16INK4 family currently includes four members, p15INK4b, pl6INK4a, pl8INK4c and p19INK4d. Two members, p15INK4b and pl6INK4a have been found to be deleted and mutated in a variety of human tumor-derived cell lines and primary tumors. In the present study we have examined the genomic status of the newly isolated p19INK4d gene in 75 tumor-derived cell lines; 13 immortalized, transformed or normal cell lines; 19 ovarian tumors and 18 acute myelogenous leukemias. No deletions or point mutations were observed in the pl9INK4d gene. A genetic polymorphism at codon 30 (CGC-->CGG) in exon 1 of the pl9INK4d gene was observed in 10% of the samples under investigation. In the same set of samples, p16INK4a was found to be homozygously deleted in 32% of the tumor derived cell lines. These results together with our previous data that showed a 22% deletion frequency in p15INK4b and rare alterations in the pl8INK4c gene, indicating that the p16INK4a and pl5INK4b, but not the p18INK4c and pl9INK4d genes, are frequently mutated in human tumors. Hence, members of the p16INK4 CDK inhibitor family, while evolutionary related and biochemically indistinguishable, carry out distinct biological functions.
 ...
PMID:Lack of mutation in the cyclin-dependent kinase inhibitor, p19INK4d, in tumor-derived cell lines and primary tumors. 893 52

Selenium, both organic and inorganic forms, inhibit mammary tumorigenesis in vivo and mammary cell growth in vitro. In the present study, sodium selenite was compared to methylselenocysteine (MSC) for their individual effects on cell growth, cdc2/cdk2 kinase activities and the levels of cyclins D1, E and A bound to cdk2 in a mouse mammary epithelial cell culture model. Selenite arrested the growth of cells in S-G2-M phase in contrast to MSC which arrested or delayed the cells in G1. In MSC-treated cells there was a 57% drop in the cdk2 kinase activity accompanied by a 73.5% decrease in cyclin E-cdk2 content as compared to the control cells. Selenite treatment increased the cdk2 kinase activity by 30% without any appreciable change in either of the cyclins D1, E or A bound to cdk2 when compared to the control cells. These data support the hypothesis that selenite and MSC have distinct modes of action in the inhibition of cell growth in vitro. Selenite has a strong genotoxic effect on the tumor cells; in contrast, MSC appears to inhibit cell growth via specific inhibition of cell cycle regulatory proteins.
 ...
PMID:Organic and inorganic selenium compounds inhibit mouse mammary cell growth in vitro by different cellular pathways. 894 25

Deregulated expression of several cell cycle regulatory genes has been demonstrated to be associated with cancer. In particular, a strong correlation has been established between inappropriate cyclin E expression and human breast cancer. To determine the ability of cyclin E to play a causative role in mammary tumorigenesis, regulatory sequences from the ovine beta-lactoglobulin gene were utilized to specifically target expression of human cyclin E to the mammary glands of pregnant and lactating mice. Lactating mammary glands of transgenic mice expressing cyclin E contained areas of hyperplasia, primarily papillary projections of hyperplastic cells, which were rarely observed in lactating glands of control mice. Over 10% of female cyclin E transgenic mice have developed mammary carcinomas, with latencies ranging from 8 to 13 months. Tumor analysis revealed the presence of transgene-specific cyclin E RNA and protein, as well as cyclin E- and cdk2-associated kinase activity, suggesting that cyclin E is likely a contributing component of tumorigenic progression in this model system.
 ...
PMID:Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. 897 26

Methylselenocysteine (MSC), an organic selenium compound has significant anticarcinogenic activity against mammary tumorigenesis. Previous experiments have demonstrated that MSC and inorganic selenite inhibit mammary cell (TM6 cell line) growth through different pathways. The present investigation demonstrated that MSC arrested cells in S phase during the TM6 cell cycle, which was followed by cells entering apoptosis at 48 h. Methylselenocysteine specifically affected the cdk2 kinase activity of the TM6 cells (54% reduction) at 16 h after release from growth arrest. The cdk4 kinase activity did not change during the cell cycle, confirming that cells had passed the G1 checkpoint and had entered S phase. The amount of cyclin E associated with cdk2 was increased by MSC by the 12 h time point, thereby facilitating entry of cells into S phase. Afterwards, cyclin E and cyclin A associated with cdk2 did not change for the remainder of the cell cycle. The data demonstrate that inhibition of mammary cell growth by MSC is mediated by alterations in progression of cells through S phase. The decrease in cdk2 kinase activity is coincident with prolonged arrest in S phase. One consequence of prolonged arrest may be apoptosis.
 ...
PMID:Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells. 927 28

The tumor suppressor p53 and its target the CDK inhibitor p21 (Cip1/Waf1) are key components of the cellular response to DNA damage. Insight into how p21 is regulated in normal cells, and how it may be deregulated in tumor cells is important for the understanding of tumorigenesis. p21 was induced in normal human diploid fibroblasts after UV irradiation-induced DNA damage, but, at a high dose of UV irradiation, a faster mobility form of p21 on SDS-PAGE (designated p21delta) was expressed. Surprisingly, in a variety of growing transformed cell lines, the level of p21 was low but p21delta was prominent. We found that p21delta appeared to be derived through a loss of around 10 amino acids from the C-terminus of p21, which theoretically would remove the PCNA binding domain, a second cyclin binding domain and the nuclear localization signal sequence. Several characteristics distinguish p21 from p21delta. Both the full length p21 and p21delta could be stabilized by a proteasome inhibitor, but only the full length p21 was associated with Cdk2 and PCNA. Consistent with this, gel filtration chromatography revealed that all the full length p21 in the cell was complexed to other proteins, whereas a significant portion of p21delta was in monomeric form. Moreover, p21 was mainly localized to the nucleus, but p21delta was mainly localized to the cytoplasm. We propose that the decrease in p21 and increase in p21delta could contribute to the deregulation of the cell cycle, and could be a mechanism involved in cellular transformation.
 ...
PMID:Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells. 954 35

During the three last years, the so-called p16 locus on human chromosome band 9p21 has been increasingly implicated in different cancers by a variety of alterations abolishing both copies of the p16INK4a/MTS1/CDKN2 gene and the adjacent p15INK4b gene, two members of a family of specific inhibitors of the cyclin D 1-3-CDK4/6 complexes that control cell cycle progression of the G1 to S phase. While these properties are characteristic of tumor suppressor genes, abundant experimental data have clearly identified a link between the loss of function of p16INK4a and tumorigenic processes. The role of p15INK4b alterations in the onset of natural and experimental tumors is less obvious. New light may be shed on the role of the p16 locus in tumor development by the recent finding that an alternative transcript from the p16INK4a gene encodes p19ARF, a negative regulator of cell cycle progression which is unrelated to p16 and p15 and does not act by binding any CDK. Hence, this protein appears to be an element of a novel negative cell cycle control mechanism, whose impairing might be involved in tumorigenesis.
 ...
PMID:Contribution of the dual coding capacity of the p16INK4a/MTS1/CDKN2 locus to human malignancies. 955 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>