Guilty as CHARGED: p53's expanding role in disease

Nostrand, Jeanine L. Van; Attardi, Laura D.

doi:10.4161/15384101.2014.987627

Cited by 19 publications

(24 citation statements)

References 85 publications

(197 reference statements)

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“…Although hyperactive p53 mutants have been described previously (reviewed in Van Nostrand and Attardi, 2014), the p53 53,54 mutant is unique in displaying enhanced tumor suppressor capability. Mice expressing either of two N-terminal deletion variants – p53 Δ40 or p53 m – display premature aging, which is at least in part attributable to effects on gene expression (Maier et al, 2004; Tyner et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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SUMMARY The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

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Section: Discussionmentioning

confidence: 99%

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

et al. 2017

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“…While these studies highlight the critical role of Chd7 in development (reviewed in (Layman et al 2010)), it is also clear that Chd7 modulates pathways central in tumorigenesis. Indeed, the CHARGE syndrome phenotypes of Chd7-compromised mice are at least partially due to enhanced p53 activity (Van Nostrand and Attardi 2014). This is reminiscent of the finding that gain of Chd5 dosage enhances p53 activity, leading to developmental abnormalities and neonatal lethality caused by over exuberant apoptosis (Bagchi et al 2007).…”

Section: Subfamily Iii: Chd6 Chd7 Chd8 Chd9mentioning

confidence: 99%

The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

Mills

2017

Cold Spring Harb Perspect Med

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A plethora of mutations in chromatin regulators in diverse human cancers is emerging, attesting to the pivotal role of chromatin dynamics in tumorigenesis. A recurrent theme is inactivation of the Chromodomain Helicase DNA-binding (CHD) family of proteins—ATP-dependent chromatin remodelers that govern the cellular machinery’s access to DNA, thereby controlling fundamental processes including transcription, proliferation, and DNA damage repair. This review highlights what is currently known about how genetic and epigenetic perturbation of CHD proteins and the pathways they regulate set the stage for cancer, providing new insight for designing more effective anti-cancer therapies.

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“…CHD7 loss in mouse NCC or samples from patients with CHARGE syndrome results in p53 activation. [7] Apoptosis also underlies ethanol-induced craniofacial malformations.…”

Section: Treacher Collins- Charge-and Fetal Alcohol Syndromementioning

confidence: 99%

Section: Treacher Collins- Charge-and Fetal Alcohol Syndromementioning

confidence: 99%

“…CHD7 loss in mouse NCC or samples from patients with CHARGE syndrome results in p53 activation. [7] Apoptosis also underlies ethanol-induced craniofacial malformations.[8] Upregulation of Siah1 by ethanol triggers apoptosis in NCCs through p38 MAPK-mediated activation of p53.[9] Thus, overactivation of p53 is the underlying mechanism for exaggerated NCC apoptosis promoting dysmorphic craniofacial features in the TCS and CHARGE syndrome as well as fetal alcohol spectrum disorders, which exhibit multiple overlapping features of isotretinoin embryopathy (Table S1). …”

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confidence: 99%

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Overexpression of p53 explains isotretinoin's teratogenicity

Melnik

2017

Experimental Dermatology

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The precise molecular basis of retinoid embryopathy is yet unknown.This hypothesis predicts that isotretinoin (13-cis retinoic acid), the prodrug of all-trans retinoic acid (ATRA), exaggerates neural crest cell (NCC) apoptosis via upregulation of the pro-apoptotic transcription factor p53, the guardian of the genome. Increased p53 signalling is associated with Treacher Collins-, CHARGE-and fetal alcohol syndrome, which exhibit dysmorphic craniofacial features resembling retinoid embryopathy. In addition, developmental studies of NCC homeostasis in the zebrafish support the pivotal role of p53. Translational evidence implies that isotretinoin-stimulated overactivation of p53 during embryogenesis represents the molecular basis of isotretinoin′s teratogenicity. | INTRODUCTIONIsotretinoin, the most effective drug for the treatment of severe acne, is teratogenic. The majority of malformations induced by isotretinoin treatment during pregnancy primarily affect neural crest cells (NCCs) leading to craniofacial dysmorphic features involving cardiac, thymic and central nervous system structures (s1-s6), which have also been observed in pigtail monkeys exposed to ATRA during gestation (s7,s8). During craniofacial development, massive cell death occurs in vertebrates (s9). In the developing nervous system a well-regulated balance of apoptotic signalling ensures appropriate cell differentiation and maturation (s10,s11). Isotretinoin-treated NCCs often became rounded or spindle-shaped, separated from their neighbours, and frequently detached from the substrate or clumped together (s12).Animal studies confirmed that administration of isotretinoin increases apoptosis of NCCs (s13-s15). It has recently been suggested that isotretinoin′s major desired and adverse drug effects including teratogenicity are related to apoptosis such as sebocyte and NCC apoptosis, respectively. [1,2] The prodrug isotretinoin is intracellularly isomerized to ATRA (s16). | ISOTRETINOIN AND P53-INDUCED APOPTOSISIn sebocytes, increased expression of the pro-apoptotic proteins tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL-receptor 1 (DR4) and insulin-like growth factor-binding pro- has been identified as a target gene of p53 (s28). Thus, isotretinoinmediated upregulation of p53 and PAX-2 may explain the NCC abnormalities reported in isotretinoin exposed macaque embryos. HOX transcription factors, which are also induced by ATRA (s29-s31), play a crucial role in NCC-dependent branchial arch pattering (s32-s35). Intriguingly, HOX binding sites have been identified on the TP53promoter and compromised HOXA5 function limited p53 expression (s36). Thus, ATRA-induced HOX gene expression may further enhance p53 expression explaining the interplay between ATRA, HOX and p53 in retinoid teratogenicity (Figure 1). NCCs and sebocytes may be especially susceptible to isotretinoin either due to their increased capacity for isomerization to ATRA (s16) or higher ATRA gradients due to decreased CYP26-mediated degradation of ATRA (s37). |...

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Guilty as CHARGED: p53's expanding role in disease

Cited by 19 publications

References 85 publications

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

Overexpression of p53 explains isotretinoin's teratogenicity

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