p21Waf1/Cip1/Sdi1 mediates shear stress-dependent antiapoptotic function

Mattiussi, Stefania; Turrini, Paolo; Testolin, L.; Martelli, Fabio; Zaccagnini, Germana; Mangoni, Antonella; Barlucchi, Laura; Antonini, Annalisa; Illi, Barbara; Cirielli, Corrado; Padrón, Julio Rodríguez; Nicolò, Chiara; Testi, Roberto; Osculati, Francesco; Biglioli, Paolo; Capogrossi, Maurizio C.; Gaetano, Carlo

doi:10.1016/j.cardiores.2003.12.008

Cited by 24 publications

(31 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell proliferation is coupled with cell cycle progression, promoted by cyclins (e.g., cyclin D1, cyclin E and cyclin A) and inhibited by cyclin-dependent kinase inhibitors (CKIs, e.g., p21 and p27) [3]. Among them, p21 plays critical roles in various biological processes, such as cell cycle control, DNA repair, antiapoptosis, differentiation and tumor suppression [4][5][6][7]. In the vascular system, p21 can block SMC proliferation in vitro and decrease restenosis in the rat model of carotid injury [8].…”

Section: Introductionmentioning

confidence: 99%

HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

et al. 2011

View full text Add to dashboard Cite

Abnormal proliferation of vascular smooth muscle cells (VSMCs) occurs in hypertension, atherosclerosis and restenosis after angioplasty, leading to pathophysiological vascular remodeling. As an important growth arrest gene, p21 plays critical roles in vascular remodeling. Regulation of p21 expression by retinoic acid receptor (RAR) and its ligand has important implications for control of pathological vascular remodeling. Nevertheless, the mechanism of RAR-mediated p21 expression in VSMCs remains poorly understood. Here, we show that, under basal conditions, RARα forms a complex with histone deacetylase 2 (HDAC2) and Krüppel-like factor 5 (Klf5) at the p21 promoter to inhibit its expression. Upon RARα agonist stimulation, HDAC2 is phosphorylated by CK2α. Phosphorylation of HDAC2, on the one hand, promotes its dissociation from RARα, thus allowing the liganded-RARα to interact with co-activators; on the other hand, it increases its interaction with Klf5, thus leading to deacetylation of Klf5. Deacetylation of Klf5 facilitates its dissociation from the p21 promoter, relieving its repressive effect on the p21 promoter. Interference with HDAC2 phosphorylation by either CK2α knockdown or the use of phosphorylation-deficient mutant of HDAC2 prevents the dissociation of Klf5 from the p21 promoter and impairs RAR agonist-induced p21 activation. Our results reveal a novel mechanism involving a phosphorylation-deacetylation cascade that functions to remove the basal repression complex from the p21 promoter upon RAR agonist treatment, allowing for optimum agonistinduced p21 expression.

show abstract

Section: Introductionmentioning

confidence: 99%

HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Undisturbed flow induces reversible growth arrest (quiescence) and protection from apoptosis via p53-mediated induction of p21 and GADD45. 45,51,52 Other studies have shown that disturbed flow promotes apoptosis via a mechanism that involves modification of p53 with SUMO (small ubiquitin-like modifier) and retention in the cytoplasm. 46 Together with our current study, which indicated a role for p53 in disturbed flowinduced senescence, these observations emphasize the pleiotropic nature of p53 which is influenced by blood flow patterns.…”

Section: Discussionmentioning

confidence: 99%

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

Warboys

Luca

Amini

et al. 2014

ATVB

176

151

View full text Add to dashboard Cite

A ging is a major risk factor for the development of cardiovascular disease, and age-related changes in vascular function are hypothesized to influence the progression of atherosclerosis. One of the hallmarks of aging tissues is an impaired ability to regenerate, caused by the accumulation of senescent cells. Cellular senescence is a state of irreversible growth arrest 1 that can be triggered via the progressive shortening of telomeres (DNA sequence repeats that protect the ends of chromosomes) with successive rounds of cell division, known as replicative senescence.2 Senescence can also be induced by a variety of cellular stresses, independently of extensive proliferation, including oxidative stress 3,4 and activation of oncogenes. 5The signaling pathways that promote cellular senescence vary according to the initiating stimulus, cellular context, and other factors. Senescence can be induced by p16 INK4A (p16) and p14 ARF /p53 signaling pathways.5-8 p16 inhibits cyclin-dependent kinases 2 and 4, whereas p53 induces the cyclin-dependent © 2014 American Heart Association, Inc. Objective-Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow-generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence. Approach and Results-LDLR−/− (low-density lipoprotein receptor −/− ) mice were exposed to a high-fat diet for 2 to 12 weeks (or to a normal chow diet as a control) before the assessment of cellular senescence in aortic ECs. En face staining revealed that senescence-associated β-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet. By contrast, ECs exposed to undisturbed flow did not express senescence-associated β-galactosidase or p53. Studies of aortae from healthy pigs (aged 6 months) also revealed enhanced senescence-associated β-galactosidase staining at sites of disturbed flow. These data suggest that senescent ECs accumulate at disturbed flow sites during atherogenesis. We used in vitro flow systems to examine whether a causal relationship exists between flow and EC senescence. Exposure of cultured ECs to flow (using either an orbital shaker or a syringe-pump flow bioreactor) revealed that disturbed flow promoted EC senescence compared with static conditions, whereas undisturbed flow reduced senescence. Gene silencing studies demonstrated that disturbed flow induced EC senescence via a p53-p21 signaling pathway. Disturbed flow-induced senescent ECs exhibited reduced migration compared with nonsenescent ECs in a scratch wound closure assay, and thus may be defective for arterial repair. However, pharmacological activation of sirtuin 1 (using resveratrol or SRT1720) protected ECs from disturbed flow-induced senescence. Conclusions-Distu...

show abstract

“…Therefore, we reasoned that p21 CIP1/WAF1 might be the molecular switch that determines the outcome of BRAF inhibition. To evaluate the role of p21 CIP1/WAF1 in the resistance to apoptosis, two adenoviral constructs were employed: one that encodes for p21 CIP1/WAF1 (Ad.p21-S) to restore p21 CIP1/WAF1 levels in A375, whereas the second one (Ad.p21-AS) encodes for an antisense transcript and was exploited to knock down p21 CIP1/WAF1 protein in ARO cells (20). Cells were simultaneously infected by the adenovirus and treated with PLX4032.…”

Section: Effects Of P21mentioning

confidence: 99%

“…Adenoviruses expressing p21 CIP1/WAF1 sense or antisense transcripts and GFP as a marker were prepared as described (20). Experiments were done by seeding 3 Â 10 5 cells in complete medium, in six-well plates.…”

Section: Adenovirus Infectionmentioning

confidence: 99%

BRAF Silencing by Short Hairpin RNA or Chemical Blockade by PLX4032 Leads to Different Responses in Melanoma and Thyroid Carcinoma Cells

Sala

Mologni

Truffa

et al. 2008

Molecular Cancer Research

176

105

View full text Add to dashboard Cite

BRAF-activating mutations have been reported in several types of cancer, including melanoma (f70% of cases), thyroid (30-70%), ovarian (15-30%), and colorectal cancer (5-20%). Mutant BRAF has constitutive kinase activity and causes hyperactivation of the mitogen-activated protein kinase pathway. BRAF silencing induces regression of melanoma xenografts, indicating the essential role of BRAF for cell survival. We set up an inducible short hairpin RNA system to compare the role of oncogenic BRAF in thyroid carcinoma versus melanoma cells. Although BRAF knockdown led to apoptosis in the melanoma cell line A375, the anaplastic thyroid carcinoma cell ARO underwent growth arrest upon silencing, with little or no cell death. Reexpression of the thyroid differentiation marker, sodium iodide symporter, was induced after long-term silencing. The different outcome of BRAF down-regulation in the two cell lines was associated with an opposite regulation of p21 CIP1/WAF1 expression levels in response to the block of the BRAF mitogenic signal. These results were confirmed using a specific BRAF small-molecule inhibitor, PLX4032. Restoration of p21 CIP1/WAF1 expression rescued melanoma cells from death. Altogether, our data indicate that oncogenic BRAF inhibition can have a different effect on cell fate depending on the cellular type. Furthermore, we suggest that a BRAF-independent mechanism of cell survival exists in anaplastic thyroid cancer cells. (Mol Cancer Res 2008;6(5):751 -9)

show abstract

p21Waf1/Cip1/Sdi1 mediates shear stress-dependent antiapoptotic function

Abstract: The present study establishes that, under our experimental conditions, (a) p21 plays an important role in SS and nitric oxide antiapoptotic effect in vitro, and (b) p21 gene transfer prevents apoptosis in vitro and in vivo, following acute interruption of blood flow.

Cited by 24 publications

References 24 publications

HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

BRAF Silencing by Short Hairpin RNA or Chemical Blockade by PLX4032 Leads to Different Responses in Melanoma and Thyroid Carcinoma Cells

Contact Info

Product

Resources

About