14‐3‐3 proteins: key regulators of cell division, signalling and apoptosis

Hemert, Martijn J. van; Steensma, H. Yde; Heusden, G. Paul H. van

doi:10.1002/bies.1134

Cited by 496 publications

(405 citation statements)

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“…1 Homologues of mammalian 14-3-3⑀ and have been found in Drosophila and Xenopus laevis, 2 suggesting these are probably ubiquitous and essential. We have examined the expression of all seven mammal 14-3-3 isoforms in human normal and cancerous lung tissues.…”

Section: Discussionmentioning

confidence: 99%

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Isoform‐specific expression of 14‐3‐3 proteins in human lung cancer tissues

Liu

Qiao

et al. 2004

Intl Journal of Cancer

158

137

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14-3-3 Proteins play important roles in a wide range of vital regulatory processes, including signal transduction, apoptosis, cell cycle progression and DNA replication. In mammalian cells, 7 14-3-3 isoforms (␤, ␥, ⑀, , , and ) have been identified and each of these seems to have distinct tissue localizations and isoform-specific functions. Previous studies have shown that 14-3-3 protein levels are higher in human lung cancers as compared to normal tissues. It is unclear, however, which of the 14-3-3 isoform(s) are overexpressed in these cancers. In our study, the levels of all seven 14-3-3 isoforms were examined by RT-PCR and Western blotting. We show that the message for only two isoforms, 14-3-3⑀ and , could be detected in normal tissues. In lung cancer biopsies, however, four isoforms, 14-3-3␤, ␥, , and , in addition to 14-3-3⑀ and , were present in abundance. The expression frequency of 14-3-3␤, ␥, and isoforms was 11, 10, 13 and 8 of the 14 biopsies examined, respectively. The data from immunohistochemical staining and Western blotting were consistent with the RT-PCR results. Given the prevalence of elevated 14-3-3 expression in human lung cancers we propose that these proteins may be involved in lung cancer tumorigenesis and that specific 14-3-3 proteins may be useful as markers for lung cancer diagnosis and targets for therapy.

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Section: Discussionmentioning

confidence: 99%

“…They can bind to a wide variety of proteins involved in signal transduction, cell cycle control, vesicular transport, DNA replication and apoptosis. [1][2][3][4][5][6][7] 14-3-3 Isoforms have distinct tissue localizations. For example, expression of 14-3-3␥ is relatively strong in brain, skeletal muscle, and heart, but weak in peripheral blood leukocytes.…”

mentioning

confidence: 99%

Isoform‐specific expression of 14‐3‐3 proteins in human lung cancer tissues

Liu

Qiao

et al. 2004

Intl Journal of Cancer

158

137

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“…Tumour growth factor alpha, found to be upregulated by VHL mutation and hypoxia in this screen, has recently been shown to have a key role in growth of renal cancers. 14-3-3-epsilon, a cell cycle inhibitor that complexes with cdc2 kinase (van Hemert et al, 2001) was downregulated by VHL mutation and provides a suppression of a second cell cycle checkpoint that would synergise with cyclin D1 changes.…”

Section: Discussionmentioning

confidence: 99%

Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene

et al. 2004

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Gene expression analysis was performed on a human renal cancer cell line (786-0) with mutated VHL gene and a transfectant with wild-type VHL to analyse genes regulated by VHL and to compare with the gene programme regulated by hypoxia. There was a highly significant concordance of the global gene response to hypoxia and genes suppressed by VHL. Cyclin D1 was the most highly inducible transcript and 14-3-3 epsilon was downregulated. There were some genes regulated by VHL but not hypoxia in the renal cell line, suggesting a VHL role independent of hypoxia. However in nonrenal cell lines they were hypoxia regulated. These included several new pathways regulated by hypoxia, including RNase 6PL, collagen type 1 alpha 1, integrin alpha 5, ferritin light polypeptide, JM4 protein, transgelin and L1 cell adhesion molecule. These were not found in a recent SAGE analysis of the same cell line. Hypoxia induced downregulation of Cyclin D1 in nonrenal cells via an HIF independent pathway. The selective regulation of Cyclin D1 by hypoxia in renal cells may therefore contribute to the tissue selectivity of VHL mutation.

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Section: Introductionmentioning

confidence: 99%

“…On the other hand, the maintenance of G2 arrest is highly p53 dependent and involves at least two of its transcriptional targets, the Cdk inhibitor p21 Waf1/ Cip1 (p21) and the adaptor protein 14-3-3 (for reviews, see Ohi and Gould, 1999;Taylor and Stark, 2001). The latter protein has been proposed to mediate nuclear exclusion of cyclin B1-Cdk1, an event thought to be necessary for blocking mitosis (Chan et al, 1999;van Hemert et al, 2001).Despite accumulating evidence suggesting that p21 could regulate DNA damage-induced G2 arrest (Bunz et al, 1998;Dulic et al, 1998;Winters et al, 1998;Chan et al, 2000;Flatt et al, 2000;Baus et al, 2003), it is widely assumed that this inhibitor does not play a direct role in inactivating mitotic cyclin-Cdk1 complexes, partly because of its low affinity toward Cdk1 (Harper et al, 1995). Indeed, p21 has been detected only in a minority of cyclin B1-Cdk1 complexes after DNA damage (Levedakou et al, 1995;Barboule et al, 1999;Flatt et al, 2000) or even after overexpression of p53 or p21 (Winters et al, 1998;Smits et al, 2000).…”

mentioning

confidence: 99%

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

Charrier‐Savournin

Château

Gire

et al. 2004

MBoC

176

137

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G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their entry into mitosis, with the concomitant risks of oncogenic transformation. According to the current model, signals elicited by DNA damage prevent mitosis by inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic regulator. We now show that normal human fibroblasts use additional mechanisms to block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This nuclear retention, which strictly depends on association with endogenous p21, prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well as its recruitment to the centrosome. In p21-deficient normal human fibroblasts and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could be readily detected at the centrosome in response to DNA damage. Therefore, in normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21 directly prevents mitosis by inactivating and maintaining the inactive state of mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic cyclins, further contributes to the establishment of a permanent G2 arrest. INTRODUCTIONCyclin B1-Cdk1 is a master mitotic regulator and is therefore an ultimate target toward which most, if not all, antiproliferative signals generated during S and G2 phase converge. In cycling cells, cyclin B1 synthesis increases during late S-early G2 phase (Pines and Hunter, 1989), but the newly formed cyclin B1-Cdk1 complexes are kept inactive by inhibitory phosphorylations on Thr 14 and Tyr 15 (Norbury et al., 1991) and by active and constant nuclear exclusion via Crm1-mediated nuclear export (Hagting et al., 1998;Yang et al., 1998). The rapid nuclear accumulation of cyclin B1-Cdk1 that occurs in prophase coincides with phosphorylation of cyclin B1 at the cytoplasmic retention sequence, which also contains its nuclear export sequence (Hagting et al., 1999; for review, see Porter and Donoghue, 2003). Nuclear import of cyclin B1-Cdk1 coincides with Cdc25 phosphatase-mediated dephosphorylation of Thr 14 and Tyr 15 on Cdk1 (Berry and Gould, 1996). Based on these observations, it has been assumed that cytoplasmic cyclin B1-Cdk1 is not active. However, both earlier and most recent work suggest that cyclin B1-Cdk1 might already be activated in the cytoplasm and most probably at the centrosome (Heald et al., 1993;De Souza et al., 2000;Hirota et al., 2003;Jackman et al., 2003).According to the current model, signals elicited by DNA damage in S and G2 phases prevent mitotic entry by inhibiting both activation (via inactivation of Cdc25) and nuclear import of cyclin B1-Cdk1 (Jin et al., 1998;Yang et al., 1998Yang et al., , 2001Deming et al., 2001). G2 arrest is initiated via phosphorylation of Cdc25 by Chk1/2 kinases, a process that does not require active p53. On the other hand, the...

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14‐3‐3 proteins: key regulators of cell division, signalling and apoptosis

Cited by 496 publications

References 83 publications

Isoform‐specific expression of 14‐3‐3 proteins in human lung cancer tissues

Isoform‐specific expression of 14‐3‐3 proteins in human lung cancer tissues

Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

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