p21<sup>Waf1/Cip1</sup> Deficiency Stimulates Centriole Overduplication

Duensing, Anette; Ghanem, Louis; Steinman, Richard A.; Liu, Ying; Duensing, Stefan

doi:10.4161/cc.5.24.3567

Cited by 29 publications

(28 citation statements)

References 42 publications

(53 reference statements)

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“…An absence of p21 has been shown to lead to polyploidy due to the uncoupling of S phase and mitosis and subsequent cell death via apoptosis (54). A recent report has also shown that p21 deficiency leads to centriole overduplication and chromosome instability (18). Although there were no cells with apoptotic appearance in our study, the type of cell death that we observed was caspase dependent, indicating that it might involve an apoptotic pathway.…”

Section: Discussioncontrasting

confidence: 53%

H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway

Fragkos

Jurvansuu

Beard

2009

Molecular and Cellular Biology

148

139

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Phosphorylation of H2AX (␥H2AX) is an early sign of DNA damage induced by replication stalling. However, the role of H2AX in the repair of this type of DNA damage is still unclear. In this study, we used an inactivated adeno-associated virus (AAV) to induce a stalled replication fork signal and investigate the function of ␥H2AX. The cellular response to AAV provides a unique model to study ␥H2AX function, because the infection causes pannuclear H2AX phosphorylation without any signs of damage to the host genome. We found that pannuclear ␥H2AX formation is a result of ATR overactivation and diffusion but is independent of ATM. The inhibition of H2AX with RNA interference or the use of H2AX-deficient cells showed that ␥H2AX is dispensable for the formation and maintenance of DNA repair foci induced by stalled replication. However, in the absence of H2AX, the AAV-containing cells showed proteosome-dependent degradation of p21, followed by caspase-dependent mitotic catastrophe. In contrast, H2AX-proficient cells as well as H2AX-complemented H2AX؊/؊ cells reacted by increasing p21 levels and arresting the cell cycle. The results establish a new role for H2AX in the p53/p21 pathway and indicate that H2AX is required for p21-induced cell cycle arrest after replication stalling.

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Section: Discussioncontrasting

confidence: 53%

H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway

Fragkos

Jurvansuu

Beard

2009

Molecular and Cellular Biology

148

139

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“…In p21 Waf1Ϫ/Ϫ MEFs, initiation of centrosome and DNA duplication is uncoupled, much like that in cells with constitutively active cyclin E/Cdk2 (13,48,68). Importantly, observations that the reintroduction of wildtype p53 into p53 Ϫ/Ϫ cells resulted in nearly complete restoration of the centrosome duplication cycle while ectopic expression of p21…”

mentioning

confidence: 85%

“…Waf1 ; similarly, ectopically expressed cyclins E and A result in elevated Cdk2 activity and centrosome amplification in p53 Ϫ/Ϫ MEFs (13,27,44,49,59,68). Likewise, oncogenes and altered tumor suppressors that hyperactivate Cdk4 and result in high frequencies of centrosome amplification include ectopically expressed Her2 (47), H-Ras V12 , v-Mos (57), MEK1 Glu217/Glu221 (58), cyclin D1 (50), and silenced MEK2 (73).…”

mentioning

confidence: 99%

Cdk2 and Cdk4 Regulate the Centrosome Cycle and Are Critical Mediators of Centrosome Amplification in p53-Null Cells

Adon

Zeng

Harrison

et al. 2010

Molecular and Cellular Biology

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The two mitotic centrosomes direct spindle bipolarity to maintain euploidy. Centrosome amplification-the acquisition of >3 centrosomes-generates multipolar mitoses, aneuploidy, and chromosome instability to promote cancer biogenesis. While much evidence suggests that Cdk2 is the major conductor of the centrosome cycle and that it mediates centrosome amplification induced by various altered tumor suppressors, the role played by Cdk4 in a normal or deregulated centrosome cycle is unknown. Using a gene knockout approach, we report that Cdk2 and Cdk4 are critical to the centrosome cycle, since centrosome separation and duplication are premature in Cdk2 ؊/؊ mouse embryonic fibroblasts (MEFs) and are compromised in Cdk4 ؊/؊ MEFs. Additionally, ablation of Cdk4 or Cdk2 abrogates centrosome amplification and chromosome instability in p53-null MEFs. Absence of Cdk2 or Cdk4 prevents centrosome amplification by abrogating excessive centriole duplication. Furthermore, hyperactive Cdk2 and Cdk4 deregulate the licensing of the centrosome duplication cycle in p53-null cells by hyperphosphorylating nucleophosmin (NPM) at Thr199, as evidenced by observations that ablation of Cdk2, Cdk4, or both Cdk2 and Cdk4 abrogates that excessive phosphorylation. Since a mutant form of NPM lacking the G 1 Cdk phosphorylation site (NPM T199A ) prevents centrosome amplification to the same extent as ablation of Cdk2 or Cdk4, we conclude that the Cdk2/Cdk4/NPM pathway is a major guardian of centrosome dysfunction and genomic integrity.

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“…The following findings suggest that Tax may trigger chromosomal separation errors in several ways. (1) We find that Tax, like the HPV E7 oncoprotein (Duensing and Munger, 2003), can induce abnormal amplification of cellular centrosomes (Peloponese, Haller and Jeang, unpublished). Centrosomal amplification is seen in diverse tumors, and is considered a frequent first step shared by many cancers in developing CIN (Storchova and Pellman, 2004).…”

Section: Tax and Chromosomal Instabilitymentioning

confidence: 99%