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)

In cells of higher eukaryotes, cyclin D-dependent kinases Cdk4 and Cdk6 and, possibly, cyclin E-dependent Cdk2 positively regulate the G1- to S-phase transition, by phosphorylating the retinoblastoma protein (pRb), thereby releasing E2F transcription factors that control S-phase genes. Here we performed microinjection and transfection experiments using rat R12 fibroblasts, their derivatives conditionally overexpressing cyclins D1 or E, and human U-2-OS cells, to explore the action of G1 cyclins and the relationship of E2F and cyclin E in S-phase induction. We demonstrate that ectopic expression of cyclin E, but not cyclin D1, can override G1 arrest imposed by either the p16INK4a Cdk inhibitor specific for Cdk4 and Cdk6 or a novel phosphorylation-deficient mutant pRb. Several complementary approaches to assess E2F activation, including quantitative reporter assays in live cells, showed that the cyclin E-induced S phase and completion of the cell division cycle can occur in the absence of E2F-mediated transactivation. Together with the ability of cyclin E to overcome a G1 block induced by expression of dominant-negative mutant DP-1, a heterodimeric partner of E2Fs, these results provide evidence for a cyclin E-controlled S phase-promoting event in somatic cells downstream of or parallel to phosphorylation of pRb and independent of E2F activation. They furthermore indicate that a lack of E2F-mediated transactivation can be compensated by hyperactivation of this cyclin E-controlled event.
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PMID:Cyclin E-induced S phase without activation of the pRb/E2F pathway. 919 74

The aim of these investigations was to identify a number of molecular markers that correlate to growth stimulation by IGF-I. For this purpose, we have selected four cell lines that respond equally well to growth stimulation by serum, but differ in their proliferative response to IGF-I. Two cell lines (R503 and R600 cells) respond to IGF-I with both DNA synthesis and cell division, a third cell line (R508 cells) can enter S phase after IGF-I, but the cells do not divide, and a fourth one (R12 cells) totally fails to respond to IGF-I with growth. Using these cell lines, all of which had an intact mitogenic response program to serum, we show that: (1) an increase in GTP/GDP ratio is an early event that distinguishes cells capable of entering S phase after IGF-I from cells that do not; (2) all cells that are induced to synthesize DNA by IGF-I have increased phosphorylation of MAP kinases, regardless of their ability to divide; (3) the same cell lines display a similar increase in cyclin A and B expression at early times after stimulation; and (4) cyclin levels and cyclin B-associated cdc2 kinase activity remain elevated at later times only in cells that undergo cell division. These results establish certain parameters of IGF-I-mediated mitogenesis and clearly separate the occurrence of DNA synthesis from cell division in certain situations.
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PMID:Molecular markers of IGF-I-mediated mitogenesis. 966 33