Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase

Ciznadija, Daniel; Zhu, Xinhua; Koff, Andrew

doi:10.4161/cc.10.16.16725

Cited by 11 publications

(11 citation statements)

References 37 publications

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“…( Figures S4F and S4G). Our observation of reduced p21 levels during S phase was consistent with previous reports in S phase arrested or synchronized cells (Ciznadija et al, 2011;Gottifredi et al, 2001Gottifredi et al, , 2004 and could be validated in additional epithelial cell lines ( Figure S4H). Synchronization in G2 provided evidence for a causative relationship between delayed p21 accumulation and cell cycle state ( Figure S4I).…”

Section: Heterogeneity In P21 Dynamics Is Determined By Cell Cycle Stsupporting

confidence: 92%

“…In this study, we highlight another layer of regulation where the p53 response is shaped according to the internal state of the cell. Despite relatively homogeneous p53 dynamics upon ionizing radiation, p21 responses were highly diverse, as has been previously reported for synchronized cell populations (Ciznadija et al, 2011) or in cancerous MCF7 cells (Stewart-Ornstein and Lahav, 2016). Using a combined computational and experimental approach to link signaling dynamics to cell cycle state and cell fate determination in thousands of unperturbed living cells, we show that S phase-specific PCNA/CRL4 cdt2 -mediated p21 degradation is sufficient to fully explain the observed heterogeneity.…”

Section: Discussionsupporting

confidence: 60%

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PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

et al. 2019

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Section: Heterogeneity In P21 Dynamics Is Determined By Cell Cycle Stsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 60%

PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

et al. 2019

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“…The degradation of p21 was significantly reduced if a specific proteasome inhibitor was employed. A proteasomal‐dependent turnover of p21 that is independent of SCF SKP2 was reported recently . The results of the present study suggest that p21 is degraded by a ubiquitin‐independent proteasomal process in HaCaT cells lacking S100A11 because: (a) no significant accumulation of ubiquitinated p21 was detectable and (b) E3 ligases involved in normal p21 turnover are also decreased in S100A11 down‐regulated HaCaT cells.…”

Section: Discussionsupporting

confidence: 71%

S100A11 is involved in the regulation of the stability of cell cycle regulator p21^CIP^1/^WAF¹ in human keratinocyte HaCaT cells

et al. 2013

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The cyclin‐dependent kinase inhibitor p21CIP1/WAF1 is a regulatory factor of the cell cycle. Its transcriptional activation and protein stability are tightly controlled by several distinct mechanisms. S100A11 is a member of the S100 family of Ca2+‐binding proteins involved in several biological processes, including cell cycle progression and signal transduction. In the present study, we show that down‐regulation of S100A11 results in the reduction of p21 protein in human HaCaT keratinocytes. It appears that a ubiquitin‐independent proteasomal degradation process is involved in p21 degradation in S100A11 down‐regulated cells. The application of a proteasome inhibitor stabilized p21 protein in these cells. Analysis of distinct signal transduction pathways revealed a disturbed phosphatidylinositol‐3‐kinase/Akt pathway after S100A11 knockdown. We determined that the glycogen synthase kinase‐3, which is negatively regulated by phosphatidylinositol 3‐kinase/Akt, was activated in cells possessing knocked‐down S100A11 and appears to be involved in p21 protein destabilization. The application of a specific inhibitor of glycogen synthase kinase 3 resulted in an increase of the p21 protein level in S100A11 down‐regulated HaCaT cells. Glycogen synthase kinase 3 is able to phosphorylate p21 at T57, which induces p21 proteasomal turnover. Mutation of the glycogen synthase kinase 3 site threonine 57 into alanine (T57A) stabilizes p21 in HaCaT cells lacking S100A11. Beside decreased p21 protein, down‐regulation of S100A11 triggered the induction of apoptosis in HaCaT cells. These observations suggest that S100A11 is involved in the maintenance of p21 protein stability and appears to function as an inhibitor of apoptosis in human HaCaT keratinocyte cells. Thus, the data shed light on a novel pathway regulating p21 protein stability.

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“…It is simplistic, however, to assume that p21 is equally induced in all phases of the cell cycle, especially when taking into consideration that the activity of the above-mentioned ligases is controlled in a cell-cycle-dependent manner. The activity of SCF Skp2 , HDM2, and CRL4 Cdt2 peaks at the beginning of and during the S phase, and could counteract the p53-mediated accumulation of p21 [ 62 , 63 , 64 ]. It has long been known that, in cells that are not challenged by exogenous damage (unperturbed cell cycle), p21 levels in the S phase remain at their lowest [ 11 ].…”

Section: P21 Levels Are Differentially Regulated During and By Celmentioning

confidence: 99%

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

Mansilla

Vega

Calzetta

et al. 2020

Genes

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p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.

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Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase

Cited by 11 publications

References 37 publications

PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

S100A11 is involved in the regulation of the stability of cell cycle regulator p21^CIP^1/^WAF¹ in human keratinocyte HaCaT cells

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

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Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase

Cited by 11 publications

References 37 publications

PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

S100A11 is involved in the regulation of the stability of cell cycle regulator p21CIP1/WAF1 in human keratinocyte HaCaT cells

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

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S100A11 is involved in the regulation of the stability of cell cycle regulator p21^CIP^1/^WAF¹ in human keratinocyte HaCaT cells