Living with or without cyclins and cyclin-dependent kinases

Sherr, Charles J.; Roberts, James M.

doi:10.1101/gad.1256504

Cited by 977 publications

(920 citation statements)

References 111 publications

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“…These steps are frequently deregulated in malignant cells and are therefore potential targets for cancer intervening drugs (Vermeulen et al, 2003). However, recent findings suggested a high functional redundancy of the G1-S regulatory components, like CDK4 and CDK2 (Berthet et al, 2003;Ortega et al, 2003;Tetsu and McCormick, 2003;Malumbres et al, 2004;Sherr and Roberts, 2004). This new insight raises the need for identification of new regulators of the G1-S transition phase.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…Cyclin/Cdk complexes are themselves negatively regulated by Cdk inhibitors such as p16 INK4A , p21 CIP1 and p27 KIP1 (Sherr and Roberts, 2004). Whilst phosphorylation is recognized as a post-translational modification that significantly influences pRb activity, it is now apparent that other types of modification can also impact upon pRb/E2F.…”

Section: Introductionmentioning

confidence: 99%

Diversity within the pRb pathway: is there a code of conduct?

2012

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The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein (pRb) pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post-translational modifications that occur on pRb together with its key effector E2F-1. Here we provide an overview of the modifications and consider the possibility of a 'code' that endows pRb with the ability to function in diverse physiological settings.

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“…Toward this end, we and others have shown that as part of its proproliferative program, androgen induces accumulation of Dtype cyclins (Knudsen et al, 1998;Xu et al, 2006). This class of cyclins interact with and activate cyclin-dependent kinases (CDK) 4/6 to promote G 1 progression during the cell cycle (Mittnacht, 1998;Sherr and Roberts, 2004). Recent studies have shown that AR stimulates cell cycle progression at least in part through induction of mTOR (mammalian Target of Rapamycin) activity, which facilitates cyclin D protein accumulation .…”

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confidence: 99%

“…Furthermore, p21 Cip1 protein levels are induced by androgen stimulation (Knudsen et al, 1998) and p21 Cip1 has been shown to be a direct AR target gene (Lu et al, 1999). Displacement of p21 Cip1 from active cyclin D1/CDK4 complexes allows p21 Cip1 to bind and inhibit CDK2 activity, thereby inhibiting progression through G 1 and into S phase (Sherr and Roberts, 2004). Thus, the ability of cyclin D1 to interact with p21 Cip1 is thought to be a critical function in promoting cellular proliferation and is often associated with mitogenic stimulation (Alt et al, 2002).…”

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confidence: 99%

Impact of differential cyclin D1 expression and localisation in prostate cancer

et al. 2007

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Cyclin D1 is a critical regulator of androgen-dependent transcription and cell cycle progression in prostate cancer cells. Despite the influence of D-type cyclins on prostate cancer proliferation, few studies have examined the expression of cyclin D1 in localised tumours or challenged its relevance to disease progression. Cyclin D1 status was characterised using immunohistochemistry in 38 non-neoplastic prostate samples, 138 primary human prostate carcinomas, and three lymph node metastatic specimens. Relevance of cyclin D1 to preoperative prostate-specific antigen (PSA) levels, Ki-67 index, and p21 Cip1 status was also examined. Cyclin D1-positive phenotype was increased in primary carcinoma compared to non-neoplastic tissue, and was evident in all lymph node metastases cases. Interestingly, at least three distinct localisation patterns were observed in the cyclin D1-positive cohort, wherein cytoplasmic localisation was identified in a large fraction, and this pattern was predominant in lower grade tumours. Relevance of altered cyclin D1 status was observed, wherein cyclin D1-positive tumours were associated with low preoperative PSA levels, consistent with in vitro reports that cyclin D1 may alter the expression of this tumour marker. Moreover, tumours with predominantly cytoplasmic cyclin D1 showed the lowest Ki-67 index, whereas nuclear cyclin D1 was associated with higher grade, elevated Ki-67, and increased nuclear p21 Cip1 . These data demonstrate that differential cyclin D1 status may influence clinicopathological parameters, and reveal new insight as to the regulation and potential consequence of cyclin D1 expression in prostate cancer.

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Living with or without cyclins and cyclin-dependent kinases

Cited by 977 publications

References 111 publications

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

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

Diversity within the pRb pathway: is there a code of conduct?

Impact of differential cyclin D1 expression and localisation in prostate cancer

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