A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2

Sexl, Veronika; Diehl, J. Alan; Sherr, Charles J.; Ashmun, Richard A.; Beach, David; Roussel, Martine F.

doi:10.1038/sj.onc.1202362

Cited by 94 publications

(96 citation statements)

References 69 publications

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“…The family of Cdc25 dualspecificity phosphatases controls the cell cycle at different phases. [5][6][7] Cdc25A was shown to regulate G1-S transition by dephosphorylating threonine 14 and tyrosine 15 of cyclindependent kinase 2 (Cdk2), [8][9][10][11][12][13] and by competition with p21 for cyclinA/Cdk2 and cylinE/Cdk2 binding sites. 14 Moreover, Cdc25A degradation is part of a DNA-damage checkpoint mechanism.…”

Section: Introductionmentioning

confidence: 99%

Subcellular localisation of Cdc25A determines cell fate

et al. 2003

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Cell division cycle 25A (Cdc25A) was shown to colocalise both with nuclear and cytoplasmic proteins. Recently, we have demonstrated that overexpressed Cdc25A promoted the survival of rat 423 cells through indirect activation of PKBprotein kinase B. Using a Cdc25A:ER fusion protein, which can be shuttled from the cytoplasm into the nucleus, the present investigation evidences that the antiapoptotic effect of Cdc25A was restricted to its cytoplasmic localisation in rat 423 cells. In contrast, nuclear Cdc25A overexpression caused dephosphorylation and nuclear retention of the proapoptotic transcription factor Forkhead in rhabdomyosarcoma-like 1 (FKHRL1) in human N.1 ovarian carcinoma cells. This resulted in the increased constitutive expression of the FKHRL1 targets Fas ligand and Bim, and promoted apoptosis. Thus, the Cdc25A oncogene, which was found to be frequently overexpressed in certain human cancers, can increase or decrease the susceptibility to apoptosis depending on the cell-type-specific subcellular distribution.

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Section: Introductionmentioning

confidence: 99%

Subcellular localisation of Cdc25A determines cell fate

et al. 2003

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“…Membranes were probed with a-cdk6 (sc-177), cdk4 (sc-260), p16 (sc-1207) and JunB (sc-73x) (Santa Cruz Biotechnologies Inc., Santa Cruz, CA, USA), p19 (Ab80; Abcam Inc., Cambridge, UK) and b-actin (Sigma A2228). For kinase assays, 800 mg of protein lysate was immunoprecipitated with antibodies against cdk2 (sc-163), cdk4 (sc-260) and cdk6 (a generous gift from M Malumbres, CNIO) as described (Sexl et al, 1999). The kinase reaction was initiated by adding 10 mCi of [g-32 p]ATP (Amersham Biosciences, GE Health care, Munich, Germany) and 1 mg histone H1 (Roche Diagnostics, Vienna, Austria) per sample for cdk2 or 1 mg p56Rb (QED Bioscience, San Diego, CA, USA) for cdk4 and cdk6, respectively.…”

Section: Preparation Of Primary Cells Infection Of Fetal Liver Cellsmentioning

confidence: 99%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

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Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB D/D ) cells induced leukemia in RAG2 À/À mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB D/D tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB D/D cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16 INK4a . These alterations were due to irreversible reprogramming of the cell, because -once established -accelerated disease induced by junB D/D cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

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“…The commercial anti-cdc25A antibodies used in our experiments did not detect cdc25A-ubiquitin conjugates, in either M1 or H1299 cells. One possible explanation is that the epitopes recognized by the antibodies were masked by ubiquitin, or, alternatively, the sensitivity of the antibodies was not su cient to detect the lower concentrations of cdc25A protein associated with ubiquitin (Sexl et al, 1999;Blomberg and Ho mann, 1999), although in some cell types there is a decrease in cdc25A protein expression (Blomberg and Ho mann, 1999). The bimodal expression kinetics of cdc25A protein is consistent with a role for cdc25A in the G1/S transition and also later in the cell cycle.…”

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confidence: 90%

“…Moreover, cdk2/cyclinE and cdk2/cyclinA complexes have been shown to be prematurely activated upon ectopic expression of cdc25A (Blomberg and Ho mann, 1999). However, whether cdk2 is an in vivo target of cdc25A which is directly activated by this phosphatase has not been conclusively shown (Sexl et al, 1999). Regarding the regulation of cdc25A expression during the cell cycle, controversial reports have been published.…”

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confidence: 99%