Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response

Cazzalini, Ornella; Scovassi, Anna Ivana; Savio, Monica; Stivala, Lucia Anna; Prosperi, Ennio

doi:10.1016/j.mrrev.2010.01.009

Cited by 378 publications

(304 citation statements)

References 146 publications

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“…Of note, also progerin, the truncated prelamin A form accumulated in HGPS cells tended to increase during DDR (Supporting Information Figure S1a–d). In this context, we evaluated the expression pattern of CDKN1A , whose modulation during DDR is a key event to avoid shift into a senescence program (Cazzalini et al, 2010). Modulation of CDKN1A levels was observed in control samples subjected to oxidative stress, where CDKN1A transcripts were significantly increased after 4‐hr H 2 O 2 treatment and returned to basal level upon stress recovery (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

“…These results suggested deregulation of CDKN1A expression. However, as proteasome‐mediated degradation of p21 is known to contribute to modulation of protein levels during DDR (Cazzalini et al, 2010), we wanted to test the possibility that proteasomal degradation of p21 could be impaired in HGPS. The same extent of proteasome‐mediated proteolysis was observed during stress recovery in control and HGPS cells, as determined by measuring protein accumulation upon MG132 treatment (Supporting Information Figure S2a).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we analyzed cells from patients affected by HGPS, a premature aging syndrome linked to LMNA mutations, and observed an altered modulation of CDKN1A , encoding p21, in HGPS under oxidative stress. p21, alternatively p21 WAF1/Cip1 , is a cyclin‐dependent kinase inhibitor that targets CDK2 and CDK1 complexes and regulates cell cycle progression at G 1 /S border (Cazzalini, Scovassi, Savio, Stivala, & Prosperi, 2010). Moreover, p21 has been shown to play a role in the maintenance of G 2 ‐phase arrest and to be the principal mediator of cell cycle blockade in response to DNA damage (Bell & Sharpless, 2007; Prives & Gottifredi, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…p21 is a potent cell‐cycle inhibitor, which is capable of inhibiting cyclin/cyclin‐dependent kinase (CDK) complexes, thereby acting as a regulator of cell cycle progression 10, 11, 12, 13. Most notably, inactivation of CyclinA/CDK2 because of binding of the N‐terminal domain of p21 results in hypophosphorylation of Retinoblastoma protein and sequestration of transcription factor E2F, thereby leading to cell cycle arrest at the G1/S phase checkpoint 10, 11, 12. The actions of p21 are complex, and it has numerous additional roles in cell cycle regulation including CDK1 and CDK 4/6 inhibition and interaction with proliferative cell nuclear antigen 10, 11, 12.…”

Section: Introductionmentioning

confidence: 99%

“…Most notably, inactivation of CyclinA/CDK2 because of binding of the N‐terminal domain of p21 results in hypophosphorylation of Retinoblastoma protein and sequestration of transcription factor E2F, thereby leading to cell cycle arrest at the G1/S phase checkpoint 10, 11, 12. The actions of p21 are complex, and it has numerous additional roles in cell cycle regulation including CDK1 and CDK 4/6 inhibition and interaction with proliferative cell nuclear antigen 10, 11, 12. Furthermore, p21 it also thought to play pivotal roles in inhibiting apoptosis, the regulation of transcription, and in DNA repair 12, 14, 15.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis

Kortum

Cloup

Williams

et al. 2018

Veterinary Internal Medicne

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BackgroundChronic hepatitis (CH) occurs commonly in dogs but is associated with a variable and largely unpredictable prognosis. p21, a cell‐cycle inhibitor and marker of cellular senescence, is upregulated in human liver disease and is a better prognostic marker than histological or clinical scoring systems.ObjectiveTo quantify hepatocyte p21 immunopositivity in histopathology samples from dogs with CH and determine its association with outcome.AnimalsTwenty‐six client‐owned dogs with histologically confirmed CH, and 15 dogs with normal liver histology.MethodsMedical records and liver histopathology samples were retrospectively reviewed to identify cases of CH. Immunohistochemistry for p21 was performed on all samples and hepatocyte immunopositivity was visually quantified. Relationships between p21 and dog age and dog survival time were statistically evaluated.ResultsHepatocyte p21 immunopositivity in dogs with CH was high (median percentage of positive hepatocytes: 90%, range: 20%‐98%) and exceeded 70% in 23/26 cases with no association with age. In control dogs, p21 immunopositivity was low (≤15% positive hepatocytes in 12/15 cases) and was positively correlated with age (r s = 0.63; P = .011). Dogs with p21 immunopositivity exceeding 91.8% (upper tercile) had significantly shorter survival compared to dogs with less than 88.9% immunopositivity (lowest tercile; 218 versus 874 days, P = .006). Increasing hepatocyte p21 immunopositivity was significantly negatively associated with survival time (HR 4.12; 95% CI 1.34‐12.63; P = .013).Conclusions and Clinical ImportanceMarked p21 immunopositivity in dogs with CH might be indicative of widespread hepatocellular senescence. A significant association with survival time also suggests a potential value for p21 quantification in determining prognosis.

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A novel enediyne‐integrated antibody–drug conjugate shows promising antitumor efficacy against CD30⁺ lymphomas

Wang

Zhang

et al. 2018

Molecular Oncology

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CD30 is a 120‐kDa type I transmembrane glycoprotein belonging to the tumor necrosis factor receptor superfamily. Overexpression of CD30 has been reported in Hodgkin's lymphoma (HL) and anaplastic large‐cell lymphoma (ALCL). CD30‐targeted treatment with antibody–drug conjugates (ADCs) can lead to promising clinical benefit. Lidamycin (LDM), consisting of an apoprotein LDP and an active enediyne chromophore AE, is a member of the enediyne antibiotic family and one of the most potent antitumor agents. AE and LDP can be dissociated and reconstituted under certain conditions in vitro. LDM is an ideal payload for the preparation of ADCs. In this study, we show the generation, production, and antitumor activity of anti‐CD30‐LDM, a novel ADC which consists of the intact anti‐CD30 antibody and LDM. First, the anti‐CD30‐LDP fusion protein was constructed and expressed in CHO/dhFr− cells. Anti‐CD30‐LDP showed specific and high‐affinity binding to CD30 and could be internalized into target cells. It also exhibited excellent tumor‐targeting capability in vivo. Next, anti‐CD30‐LDM was prepared by assembling the enediyne molecule AE to the fusion protein anti‐CD30‐LDP. Anti‐CD30‐LDM was highly cytotoxic to HL and ALCL cell lines, with IC50 values of 5–50 pm. It can also induce cell apoptosis and G2/M cell cycle arrest. In the Karpas299 xenograft model, the tumor growth was inhibited by 87.76% in mice treated with anti‐CD30‐LDM and with no discernible adverse effects. Taken together, anti‐CD30‐LDM shows attractive tumor‐targeting capability and antitumor efficacy both in vitro and in vivo and could be a promising candidate for the treatment of CD30+ lymphomas.

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Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response

Cited by 378 publications

References 146 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis

A novel enediyne‐integrated antibody–drug conjugate shows promising antitumor efficacy against CD30⁺ lymphomas

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Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response

Cited by 378 publications

References 146 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis

A novel enediyne‐integrated antibody–drug conjugate shows promising antitumor efficacy against CD30+ lymphomas

Contact Info

Product

Resources

About

A novel enediyne‐integrated antibody–drug conjugate shows promising antitumor efficacy against CD30⁺ lymphomas