Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb

Ezhevsky, Sergei A.; Nagahara, Hikaru; Vocero-Akbani, Adita M.; Gius, David; Wei, Michael C.; Dowdy, Steven F.

doi:10.1073/pnas.94.20.10699

Cited by 252 publications

(234 citation statements)

References 38 publications

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“…D-type cyclins associate with cdk4 or cdk6 to form active complexes, which phosphorylate transcriptional repressors of the Rb-family (Ezhevsky et al, 1997). Surprisingly, we observed decreased expression levels of the D-type cyclins D2 and D3 in junB D/D cells.…”

Section: Discussionmentioning

confidence: 54%

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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Section: Discussionmentioning

confidence: 54%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

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“…29 --31 This is because of failure to phosphorylate Rb by the cyclin D Cdk4/6 complex first and by the Cyclin E Cdk2 complex at the end of G1. 32 This is a consequence of persistent accumulation of p21 and induction of other Cdk inhibitors such as p16 INK4a and p15 INK4b by pERK1/2. 30,33 --35 As shown in Figure 2d BAG3 silencing results in sustained strong ERK1/2 activation that in turn results in failure to phosphorylate Rb.…”

Section: Bag3 Silencing Inhibits Tumour Growth and Neo-angiogenesismentioning

confidence: 99%

BAG3 controls angiogenesis through regulation of ERK phosphorylation

et al. 2012

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BAG3 is a co-chaperone of the heat shock protein (Hsp) 70, is expressed in many cell types upon cell stress, however, its expression is constitutive in many tumours. We and others have previously shown that in neoplastic cells BAG3 exerts an antiapoptotic function thus favoring tumour progression. As a consequence we have proposed BAG3 as a target of antineoplastic therapies. Here we identify a novel role for BAG3 in regulation of neo-angiogenesis and show that its downregulation results in reduced angiogenesis therefore expanding the role of BAG3 as a therapeutical target. In brief we show that BAG3 is expressed in endothelial cells and is essential for the interaction between ERK and its phosphatase DUSP6, as a consequence its removal results in reduced binding of DUSP6 to ERK and sustained ERK phosphorylation that in turn determines increased levels of p21 and p15 and cell-cycle arrest in the G1 phase.

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“…These two complexes together with CDK4-6/cyclin D1 (Ezhevsky et al, 1997) are engaged in the onset and maintenance of the phosphorylation state of pRB. Phosphorylation of pRB releases E2Fs (Reed, 1997;Yamasaki, 2003), which in turn activate transcription of genes involved in the onset and regulation of DNA replication (Herrera et al, 1996).…”

Section: Fer Maintains G1-s Transition In Malignant Cells O Pasder Et Almentioning

confidence: 99%

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclindependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1a was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1a and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

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Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb

Cited by 252 publications

References 38 publications

JunB is a gatekeeper for B-lymphoid leukemia

JunB is a gatekeeper for B-lymphoid leukemia

BAG3 controls angiogenesis through regulation of ERK phosphorylation

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

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