To cycle or not to cycle: a critical decision in cancer

Malumbres, Marcos; Barbacid, Mariano

doi:10.1038/35106065

Cited by 1,323 publications

(1,199 citation statements)

References 109 publications

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“…Aberrant signalling promotes activation of CDK-cyclin complexes, which phosphorylate Rb and attenuate its capacity to induce transcriptional repression. The notion that Rb phosphorylation is a convergence point for these oncogenic signalling pathways is consistent with the fact that inactivation of the RB gene by mutation or methylation is a common occurrence in cancer [18]. The inactivation of tumour suppressor genes that encode CDKIs (eg p15, p16 and p27) are also common events in diverse tumour types.…”

Section: Introductionsupporting

confidence: 55%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

579

406

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Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

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Section: Introductionsupporting

confidence: 55%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

579

406

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“…These events all result in inactivation of the pRB tumour suppressor, which gives growth advantage and allows bypass of cellular senescence pathways (Malumbres and Barbacid, 2001), and are believed to represent an early event in tumour development (Phillips et al, 1994). Interestingly, the deletion of one RB1 allele in mouse prostate gives rise to focal prostate hyperplasia, but these lesions do (RbSi3 þ pE2F3a).…”

Section: Discussionmentioning

confidence: 99%

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

et al. 2006

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Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/ FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.

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“…Cyclin D1, Cdk4 and c-Myc levels are raised in approximately 50% of HCCs (Tiniakos et al, 1993;Ito et al, 1999). Concomitantly, pRb is functionally inactivated in a majority of HCCs (Malumbres and Barbacid, 2001; Thorgeirsson and Grisham, 2002;Edamoto et al, 2003). Approximately, 40% of HCCs display microsatellite instability (MSI) or inactivating mutations in the mismatch repair genes, hMSH2 and hMLH1 (Macdonald et al, 1998;Yamamoto et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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To cycle or not to cycle: a critical decision in cancer

Cited by 1,323 publications

References 109 publications

The cell cycle and cancer

The cell cycle and cancer

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

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