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

A novel, brain-specific cDNA, denoted CROC-4, was cloned from human brain by a contingent replication of cDNA procedure capable of detecting transcriptional activators of the human c-fos proto-oncogene promoter. CROC-4 encoded an 18-kDa serine/threonine-rich polypeptide containing a P-loop motif and an SH3-binding region with phosphorylation sites for a variety of protein kinases (cdc2, CDK2, MAPK, CDK5, protein kinase C, Ca(2+)/calmodulin protein kinase 2, casein kinase 2) involved in cell proliferation and differentiation. Immunohistochemistry revealed that during early development, expression was associated with proliferating and migrating cells throughout the rodent brain, initially appearing in the proliferative ventricular zones. During late development and in adult human brain, CROC-4 was expressed in diverse brain regions including the thalamus, subthalamic nucleus, corpus callosum, substantia nigra, caudate nucleus, amygdala, and hippocampus. The association of CROC-4 expression with proliferating regions of developing brain and retention in regions of the adult brain, as well as the punctate nuclear location, suggest that CROC-4 participates in brain-specific c-fos signaling pathways involved in cellular remodeling of brain architecture.
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PMID:CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types. 1099 46

The YWK-II cDNA, RSD-2, encoding a sperm membrane protein was isolated from a rat testis cDNA expression library. Using the RSD-2 insert in combination with rapid amplification of cDNA ends (RACE), the corresponding human gene was isolated from a human testis cDNA expression library. The human testis cDNA, HSD-2, is 3654 bp in length and contains an open reading frame of 763 codons. Hydropathicity analysis showed that the deduced polypeptide is a single strand transmembrane protein. The deduced polypeptide has partial homology with the amyloid precursor protein (APP) and high homology with the amyloid precursor homologue, APLP2/APPH. The YWK-II gene was mapped and assigned to human chromosome locus: 11q24-25. Northern blotting of various human tissue RNAs using the HSD-2 cDNA as a probe showed that the gene is transcribed ubiquitously. The cytoplasmic domain of HSD-2 was expressed in Escherichia coli. In-vitro studies showed that the recombinant polypeptide bound to a GTP-binding protein (G(o)) and was phosphorylated by protein kinase C and cdc2 kinase. In mammalian F11 cells, the recombinant polypeptide was found to be coupled to G(o). Thus, the YWK-II component has the characteristics of a G(o)-coupled receptor and may be involved in G(o)-mediated signal transduction pathway. Protein kinase C and cdc2 kinase may regulate this pathway in spermatozoa by phosphorylating the cytoplasmic domain of the YWK-II component.
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PMID:Expression and characterization of the human YWK-II gene, encoding a sperm membrane protein related to the alzheimer betaA4-amyloid precursorprotein. 1110 89

The mitogen-activated protein (MAP) kinase ERK2 is an essential signal transduction molecule that mediates extracellular signaling by all polypeptide growth factors. Full activation of ERK2 requires phosphorylation at both a threonine residue (Thr(183)) conserved in most protein kinases as well as a tyrosine residue (Tyr(185)) unique to members of the mitogen-activated protein kinase family. We have characterized the kinetic role of phosphorylation at each site with respect to the overall activation mechanism, providing a complete picture of the reaction steps involved. Phosphorylation at Tyr(185) serves to configure the ATP binding site, while phosphorylation at both residues is required to stabilize binding of the protein substrate, myelin basic protein. Similar control mechanisms are employed to stabilize ATP and myelin basic protein in the phosphoryl group transfer reaction, accounting for the enormous increase in turnover rate. The mechanism of ERK2 activation is kinetically similar to that of the cell cycle control protein, cdk2/cyclinA. Phosphorylation of Tyr(185) in ERK2 and association of cyclinA with cdk2 both serve to stabilize ATP binding. Subsequent phosphorylation of both enzymes on threonine serves to stabilize binding of the phosphoacceptor substrate.
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PMID:The complete pathway for catalytic activation of the mitogen-activated protein kinase, ERK2. 1152 22

The TaCRK3 gene from the bovine apicomplexan parasite Theileria annulata, encodes a 46 kDa polypeptide with strong homology to the eukaryotic family of cyclin-dependent kinases. TaCRK3 does not show significant alignment with any particular CDK group, other than the Pfmrk kinases from the related apicomplexans Plasmodium falciparum and Plasmodium yoelii. It has a putative bipartite nuclear localization signal and is located to parasite nuclei by IFAT. Protein levels are constitutive throughout differentiation of the intra-lymphocytic macroschizont. This contrasts with the expression pattern of TaCRK2 (Kinnaird et al., 1996, Mol. Microbiol., 22, 293-302) which is closely related to the eukaryotic CDK1 /2 families involved in regulation of cell cycle progression. TaCRK2 is also located to the parasite nuclei but has no nuclear localization signal and exhibits transient up-regulation in protein levels during mid-merogony. However compared to TaCRK3, it shows down-regulation near the end of merogony. We predict that TaCRK3 may have a role in regulation of gene transcription while TaCRK2 is more likely to be involved in control of parasite nuclear division.
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PMID:TaCRK3 encodes a novel Theileria annulata protein kinase with motifs characteristic of the family of eukaryotic cyclin dependent kinases: a comparative analysis of its expression with TaCRK2 during the parasite life cycle. 1173 37

Entry into mitosis is regulated by inhibitory phosphorylation of cdc2/cyclin B, and these phosphorylations can be mediated by the Wee kinase family. Here, we present the identification of Drosophila Myt1 (dMyt1) kinase and examine the relationship of Myt1 and Wee1 activities in the context of cdc2 phosphorylation. dMyt1 kinase was found by BLAST-searching the complete Drosophila genome using the amino acid sequence of human Myt1 kinase. A single predicted polypeptide was identified that shared a 48% identity within the kinase domain with human and Xenopus Myt1. Consistent with its putative role as negative regulator of mitotic entry, overexpression of this protein in Drosophila S2 cells resulted in a reduced rate of cellular proliferation while the loss of expression via RNA interference (RNAi) resulted in an increased rate of proliferation. In addition, loss of dMyt1 alone or in combination with Drosophila Wee1 (dWee1) resulted in a reduction of cells in G2/M phase and an increase in G1 phase cells. Finally, loss of dMyt1 alone resulted in a significant reduction of phosphorylation of cdc2 on the threonine-14 (Thr-14) residue as expected. Surprisingly however, a reduction in the phosphorylation of cdc2 on the tyrosine-15 (Tyr-15) residue was only observed when both dMyt1 and dWee1 expression was reduced via RNAi and not by Wee1 alone. Most strikingly, in the absence of dMyt1, Golgi fragmentation during mitosis was incomplete. Our findings suggest that dMyt1 and dWee1 have distinct roles in the regulation of cdc2 phosphorylation and the regulation of mitotic events.
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PMID:Identification of Drosophila Myt1 kinase and its role in Golgi during mitosis. 1188 91

The astrocytomas represent the most common primary tumors of the brain. Despite efforts to improve the treatment of astrocytomas, these tumors and in particular the high-grade astrocytoma termed glioblastoma multiforme still carry a poor prognosis. In recent years, there has been an intensive effort to gain an understanding of the cellular and molecular mechanisms that contribute to the pathogenesis of astrocytomas as a first step toward the development of better treatments for these devastating tumors. Here, we will review our current understanding of the signaling pathways that underlie glial transformation. Studies of astrocytomas have led to the identification of two major groups of signaling proteins whose abnormalities contribute to gliomagenesis: the cell cycle pathways and the growth factor-regulated signaling pathways. Among the cell cycle proteins, the p16-cdk4-pRb and ARF-MDM2-p53 cell cycle arrest pathways play a prominent role in glial transformation. In addition, deregulation of polypeptide growth factors acting via receptor tyrosine kinases (RTKs) and of intracellular signals, including the lipid phosphatase PTEN, that regulate cellular responses to RTKs plays a critical role in gliomagenesis. In addition to the identification of the signaling proteins targeted in glial transformation, the cell-of-origin of astrocytomas has been investigated. Genetic modeling of astrocytomas in mice suggests that neuroepithelial precursor cells represent preferred cellular substrates of gliomas or that either astrocytes or precursor cells constitute potential cells-of-origin of astrocytomas. During normal brain development, neuroepithelial precursor cells, including neural stem cells, differentiate into astrocytes. As the mechanisms that control gliogenesis during normal brain development become better understood, it will be important to determine if deregulation of these mechanisms might contribute to the pathogenesis of astrocytomas. The elucidation of the molecular underpinnings of astrocytomas holds the promise of improved treatment options for patients with these devastating brain tumors.
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PMID:Signaling pathways regulating gliomagenesis. 1255 76

PCTAIRE 3 is a member of the PCTAIRE subfamily of cdc2-related serine/threonine protein kinases. In the present study, cDNAs encoding two isoforms of PCTAIRE 3 have been cloned and the genomic organization of the human PCTAIRE 3 gene is reported. The gene spans 28.15 kb on chromosome 1q31-32 and contains 16 exons. The major transcript of PCTAIRE 3, designated PCTAIRE 3a, has an open reading frame that is 474 amino acids in length. Transcripts for PCTAIRE 3a were evident throughout the brain and in the majority of tissues analyzed. A second transcript containing an insert that adds 90 nucleotides to the third exon of the gene was also identified. This transcript, designated PCTAIRE 3b, encodes a polypeptide of 504 amino acids. Expression of PCTAIRE 3b was limited to several subcortical nuclei of the basal gangli and the spinal cord and substantial levels of this transcript were not evident outside of the central nervous system. Primary sequence comparisons between different cdc2-related serine/threonine protein kinases reveal that these proteins are most heterogeneous in their N-terminal domains and the PCTAIRE subfamily is further diversified by the presence of isoforms within this region.
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PMID:Cloning and expression analysis of two novel PCTAIRE 3 transcripts from human brain. 1501 84

Since little is known about the function of polypeptide growth factors as regulators of multiple cell cycles, we compared the ability of FGF1, PDGF-AB and serum to induce a second round of DNA synthesis in Swiss 3T3 cells previously exposed to either FGF1, PDGF-AB or serum during the first cell cycle using [14C]- and [3H]thymidine in a double labeling system to distinguish between the first and second cell cycles. Surprisingly, we observed that cells exposed to either FGF1 or PDGF-AB in the first cell cycle were unable to synthesize DNA in response to FGF1 or PDGF-AB in the second cell cycle; yet these cells responded well to serum as a second cycle mitogen. Interestingly, while cells exposed to either FGF1 or PDGF-AB in the second cycle displayed normal receptor-mediated signaling and expressed cyclin D and E, they, like senescent fibroblasts and endothelial cells, failed to express cyclin A, and the continuous exposure of cells to either FGF1 or PDGF-AB resulted in a decrease in the kinase activity of the cyclin E/cdk2 complex. In addition, an increased association of this complex was observed with p21 CIP in an FGF1-dependent manner as well as with p27 KIP in a PDGF-AB-dependent manner. Lastly, the downregulation of p21 expression using an antisense strategy was able to partially rescue the replicative response of Swiss 3T3 cells to FGF1 in the second cycle. These data suggest that (i) FGF1 and PDGF-AB may limit their mitogenic effect to a single cell cycle, (ii) entry into the second round of replication is serum dependent and (iii) the self-limiting nature of FGF1 and PDGF-AB correlates with the accumulation of the cdk inhibitors, p21 and p27, respectively.
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PMID:Stimulation of quiescent cells by individual polypeptide growth factors is limited to one cell cycle. 1550 56

Mcl-1 (myeloid cell leukaemia-1) is a Bcl-2 family member with short-term pro-survival functions but whose other functions, demonstrated by embryonic lethality of knockout mice, do not involve apoptosis. In the present study, we show a cell-cycle-regulatory role of Mcl-1 involving a shortened form of the Mcl-1 polypeptide, primarily localized to the nucleus, which we call snMcl-1. snMcl-1 interacts with the cell-cycle-regulatory protein Cdk1 (cyclin-dependent kinase 1; also known as cdc2) in the nucleus, and Cdk1 bound to snMcl-1 was found to have a lower kinase activity. The interaction with Cdk1 occurs in the absence of its cyclin partners and is enhanced on treatment of cells with G2/M blocking agents, but not by G1/S blocking. The snMcl-1 polypeptide is present during S and G2 phases and is negligible in G1. Overexpression of human Mcl-1 in a murine myeloid progenitor cell line resulted in a lower rate of proliferation. Furthermore, Mcl-1-overexpressing cells had lower total Cdk1 kinase activity compared with parental cells, in both anti-Cdk1 and anti-cyclin B1 immunoprecipitates. The latter results suggest that binding to snMcl-1 alters the ability of Cdk1 to bind its conventional partner, cyclin B1. Given the important role of Cdk1 in progression through G2 and M phases, it is probable that the inhibition of Cdk1 activity accounts for the inhibitory effect of Mcl-1 on cell growth.
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PMID:A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1. 1555 78

Breast cancer is the most common malignancy and the second major cause of cancer-related deaths among women in the United States. Recent advances in the molecular genetics of breast cancer have identified various genes associated with tumorigenesis. There is evidence that non-steroidal anti-inflammatory drugs, e.g. sulindac, have some anti-proliferative effects on various tumors involving altered p53 function. Most of these studies have been performed with various human colon carcinoma cell lines and few of them focus on non-malignant proliferative human mammary epithelial cell lines. Therefore, the present study was undertaken to analyze the differentially expressed genes of the p53 signaling pathway by means of a gene array for the immortalized human breast epithelial cell line, MCF-10F, treated with sulindac. Out of the total 96 genes, only 17 were altered by the drug treatment. Among these 17 genes, 6 showed significant alteration (Q > 2.0), whereas 11 genes showed moderate alterations. Altered genes included BRCA1 associated protein-1 [ubiquitin carboxy-terminal hydrolase (bap1)]; cell division cycle 2, G1 to S and G2 to M [cdk1(cdc2)]; and DNA-damage-inducible transcript 1 (gadd45), which were down-regulated. However, N-myc gene 1 (rtp), promyelocytic leukemia (pml), and nuclear factor of kappa-light polypeptide gene enhancer in B-cell 3 and p65 [avian (rel A)] were up-regulated. Northern blot analysis confirmed some of these alterations. The alteration of p53 signaling pathway gene markers by sulindac treatment can give us valuable information about the response to drug treatments in a proliferative cell population.
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PMID:Differential gene expression of sulindac-treated human breast epithelial cells. 1627 29


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