Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cyclin D1 has been associated with a wide variety of proliferative diseases but its biochemical role is unknown. In diploid fibroblasts we find that cyclin D1 is complexed with many other cellular proteins. Among them are protein kinase catalytic subunits CDK2, CDK4 (previously called PSK-J3), and CDK5 (also called PSSALRE). In addition, polypeptides of 21 kd and 36 kd are identified in association with cyclin D1. We show that the 36 kd protein is the proliferating cell nuclear antigen, PCNA. Cyclin D3 also associates with multiple protein kinases, p21 and PCNA. It is proposed that there exists a quaternary complex of D cyclin, CDK, PCNA, and p21 and that many combinatorial variations (cyclin D1, D3, CDK2, 4, and 5) may assemble in vivo. These findings link a human putative G1 cyclin that is associated with oncogenesis with a well-characterized DNA replication and repair factor.
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PMID:D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. 135 58

Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1's possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation.
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PMID:PRAD1 (cyclin D1): a parathyroid neoplasia gene on 11q13. 148 73

p34cdc2 is a protein kinase that has an important role in controlling cell cycle progression and may regulate tumor suppressor gene activity. In this work, we show that the arrest of cell growth and induction of differentiation in a tumorigenic neuroblastoma cell line by retinoic acid (RA) is associated with a 75-fold decrease in the level of p34cdc2 protein. The RA induced decrease in p34cdc2 levels does not simply reflect the arrest of cell growth, because p34cdc2 levels are not reduced when neuroblastoma cells are growth arrested by nutrient deprivation. Furthermore, dephosphorylation of the tumor suppressor gene product RB, a substrate for the p34cdc2 kinase activity, is observed only when p34cdc2 levels are decreased in RA treated cells. These studies link regulation of cdc2 level, RB phosphorylation state, and induction of differentiation by RA and suggest that alterations in the cdc2 gene or in genes controlling its regulation contribute to tumorigenesis.
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PMID:Retinoic acid negatively regulates p34cdc2 expression during human neuroblastoma differentiation. 175 5

Hydrolysis of the neurotransmitter acetylcholine by acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) is the rate-limiting step in the termination of cholinergic signaling at neuromuscular junctions. A growing body of evidence suggests that these enzymes also play a role in tumorigenesis. The ACHE and BCHE genes are amplified, mutated, and/or aberrantly expressed in a variety of human tumor types. These changes could be the result of chromosome breakage, since there is an unusually high frequency of chromosomal abnormalities near the map positions of these genes (3q26-ter and 11p-ter, respectively) in such tumors, particularly hemopoietic malignancies. Both ACHE and BCHE contain the consensus peptide motif S/T-P-X-Z, which is found in many substrates of cdc2-related protein kinases. Here we consider the intriguing possibility that phosphorylation by cdc2-related kinases may be the molecular mechanism linking cholinesterases with tumor cell proliferation. We also discuss the notion that inhibition of these enzymes by commonly used organophosphorous poisons may be tumorigenic in humans.
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PMID:A role for cholinesterases in tumorigenesis? 182 94

How does a quiescent cell decide to re-enter the cell cycle and start replicating its DNA? What controls cell proliferation? These are fundamental questions that have to be solved in order to understand the mechanisms of oncogenesis. Some recent data have provided clues about how signal transduction pathways may be connected to the cell cycle. A protein kinase cascade starting from the membrane growth factor receptor is thought to be involved in transducing extracellular stimuli to the master switches of the cell cycle control machinery. The recently identified extracellular-signal regulated kinases (ERKs) appear to play an important role in this pathway. Expression of cyclins, which are regulatory subunits of the universal cell cycle oscillator cdc2, may also be controlled through this kinase cascade. The products of tumor suppressor genes Rb and p53 also play an important role in regulating cell proliferation by interfering with the cell cycle pathway. Here, I will review and discuss the importance of these different new results.
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PMID:From growth to cell cycle control. 184 42

In this paper, we review our findings concerning the control of meiosis reinitiation in starfish oocytes and discuss recent advances that lead to characterization of the maturation promoting factor (MPF) responsible for G2-M transition. It is now agreed that appearance of this factor, which triggers nuclear envelope breakdown, chromosome condensation and metaphase spindle formation, corresponds to the activation of a M-phase specific H1-kinase. MPF has been shown to be constituted of equimolar amounts of a 34 kDa catalytic subunit protein homologous to the yeast cdc2/CDC28 gene product and a cyclin protein homologous to the yeast cdc13 gene product. "In vivo" and "in vitro" studies based on the use of inhibitors of protein synthesis, protein kinases, phosphoprotein phosphatases and proteases lead to a better understanding of the complex series of events which regulate activation and inactivation of MPF. In the unfertilized metaphase 2-arrested vertebrate oocyte, it has also been shown that stabilization of MPF depends on the kinase activity of the c-mos protooncogene. This review attempts to illustrate how the significant progress made in the understanding of the regulation of cell cycle transverse directly resulted from the convergence of observations in multidisciplinary studies in yeast genetics, development and oncogenesis. It also offers a model for considering the highly integrated events which, starting at the level of the plasma membrane, may eventually result in early cell differentiation.
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PMID:Meiosis reinitiation as a model system for the study of cell division and cell differentiation. 220 65

Deregulated expression of G1 cyclins D1 and D2 is a feature of some neoplasias. This study examined the altered expression of D1 and D2 cyclins, both the total pool and as associated with cdk4 and cdk2, at different stages of mouse mammary tumorigenesis. Three different mammary hyperplastic outgrowth lines, TM2, TM10 and TM12, and their respective tumors were examined. Increasing levels of the cyclin D1 protein pool, D1 binding to cdk4 and cdk2 and cdk4 kinase activity were closely correlated with tumorigenesis. In constrast, cyclin D2 binding to cdk4 was predominant in hyperplasias and much less in tumors, where cyclin D1 became predominant. However, the cyclin D2 pool showed increases of 15-65 times in hyperplasias compared with normal gland and further increases of 11-15 times in two of three different tumors. The message level for cyclin D1 increased only 2-3 times in tumors compared with normal gland. Cyclin D2 mRNA was highest in normal tissue and decreased only marginally in tumors. These results suggest that cyclin D2 functions uniquely from cyclin D1 in the early stages of mouse mammary tumor development. Cyclin D2 bound to cdk4 may act to guarantee a low level of kinase activity in hyperplasias and may be an attempt to direct the mammary epithelial cells through differentiation rather than proliferation. This interaction may be one of the negative regulatory mechanisms in the early stages in mouse mammary tumor development, until cyclin D1 totally replaces cyclin D2 binding to cdk4, which would activate the high levels of cdk4 kinase activity observed in neoplasias.
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PMID:Mouse mammary hyperplasias and neoplasias exhibit different patterns of cyclins D1 and D2 binding to cdk4. 758 59

The CDKN2 gene located on chromosome 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16. This gene is a putative tumor-suppressor gene because of its frequent alterations in many kinds of tumor cell lines. We analyzed the CDKN2 gene to evaluate its alterations in 52 primary specimens of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) of B-cell origin by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. By Southern blot analysis, we showed homozygous deletion of the CDKN2 gene in 3 of 42 patients with B-NHL (7.1%). After screening by PCR-SSCP analysis, direct sequencing identified one missense mutation at codon 72 (nucleotide 233) and two frameshifts due to a 35-bp deletion arising at codon 49 (nucleotides 163 to 175) in patients with B-NHL (3 of 42, 7.1%). In the patient carrying the missense mutation, hemizygous deletion of the CDKN2 gene was also suspected. In this study, we detected alterations in CDKN2 in 6 of 42 patients (14.3%) with B-NHL and in none of 10 patients with B-CLL. Our results suggest that the CDKN2 alterations contribute in tumorigenesis in some patients with B-NHL.
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PMID:Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas. 767 Jan 11

Breast cancer in humans, as in mice and rats, is thought to be the result of sequential changes in the epithelial cells of the mammalian glands. This study examines the altered expression or activation of cell cycle related proteins in an in situ system composed of hyperplasia, preneoplasia and neoplasia of mouse mammary glands. The results showed a high level of cdc2/cdk2 kinase activities in tumors compared to hyperplasias which was independent of cdc2/cdk2 protein levels. Some of the cdk-associated proteins which are thought to regulate cdk kinase activity were examined in these tissues. Cyclin A was overexpressed in all hyperplasias irrespective of their tumorigenic potentials. However, a number of alterations in cyclin E protein were associated with cdk2 and its associated kinase activity during mammary tumorigenesis. First, the level of normal cyclin E (p50) expression was positively correlated with the tumorigenic potentials of different hyperplasia lines. Second, several cyclin E isoforms (p48, p43, p35, p34, p32) were detected only in tumor tissues. Third, a 2.3- and 8.3-fold increase in cyclin E-associated cdk2 kinase activity was present in highly tumorigenic hyperplasias and neoplasias respectively compared to the low tumorigenic hyperplasias. Polymorphic cell nuclear antigen (PCNA) protein bound to cdk2 was a better indicator for cell proliferation and cdk2 kinase activity than the PCNA labeling index. These results suggest a sequential pattern of multiple derangements in factors regulating cdk2 protein function during mammary tumorigenesis. High levels of cdk2 kinase activity are observed only in tumors and appear to be closely related to alterations in cyclin E protein expression.
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PMID:Cell cyclins and cyclin-dependent kinase activities in mouse mammary tumor development. 772 62

The D-type cyclins are growth factor-regulated delayed early functions which peak at the G1/S transition, are thought to regulate entry into S phase and have been implicated in tumorigenesis. Here, we show that cyclin D2 can co-operate with Ha-Ras to impose a novel transformed state on rat embryo fibroblasts (REF). While clonal cyclin D2/Ha-Ras REF transformants exhibit a characteristic transformed phenotype in high serum, in low serum they arrest cell proliferation and display profound morphological and cytological changes indicating loss of control of cell mass and deregulation of the G1/S transition. Notably, in low serum, despite re-establishment of actin cables and arrest of proliferation, cell mass continues to increase, creating giant cells up to 10 x normal size. Also, during low-serum culture the cells make a very gradual but progressive entry into S phase, reaching a 2.4N DNA content after 6 days. PCNA is expressed and 2N and 4N cells are largely absent, and thus the cells undergo a novel S phase arrest. While transfer to low serum induced the retinoblastoma protein to enter its dephosphorylated state, and cyclin A, cyclin B and cdc2 levels to decrease, all as normal, cyclin E, cdk4, cdk2 and the exogenous cyclin D2 persisted at high levels. These results indicate that cyclin D2 and Ha-Ras can transform cells when mitogenic signals from growth factors are provided. However, in low serum, co-operation of cyclin D2 and Ha-Ras provides only a subset of the progression signals and these are sufficient for G1-related cell mass increase and S phase entry, but are insufficient for full cell cycling.
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PMID:Cyclin D2 and Ha-Ras transformed rat embryo fibroblasts exhibit a novel deregulation of cell size control and early S phase arrest in low serum. 774 96


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