Dysfunction of the MDM2/p53 axis is linked to premature aging

Lessel, Davor; Wu, D. Christine; Trujillo, Carlos; Ramezani, Thomas; Lessel, Ivana; Alwasiyah, Mohammad Khalid; Saha, Biswarup; Hisama, Fuki M.; Rading, Katrin; Goebel, Ingrid; Schütz, Petra; Speit, Günter; Högel, Josef; Thiele, Holger; Nürnberg, Gudrun; Nürnberg, Peter; Hammerschmidt, Matthias; Zhu, Yuyan; Tong, David; Katz, Chen; Martin, George M.; Oshima, Junko; Prives, Carol; Kubisch, Christian

doi:10.1172/jci92171

Cited by 60 publications

(58 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exceptions to the above are the p53/p44 and the AT‐1 sTg systems. In the case of p53/p44, the primary defect is in the N‐terminal regulatory functions of the p53 protein, which leads to reduced stemness potential of stem cells as well as hyperactivation of IGF‐1R signaling (Campisi, 2004; Lessel et al, 2017; Maier et al, 2004; Pehar, Ko, Li, Scrable, & Puglielli, 2014; Tyner et al, 2002). AT‐1 sTg mice display many features that are in line with classical segmental progerias, such as reduced growth, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

View full text Add to dashboard Cite

The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The International Registry of Werner Syndrome has identified a series of distinct genetic mutations responsible for a range of novel segmental progeroid syndromes among samples submitted to our International Registry from physicians all over the world in order to rule in or rule out a diagnosis of the Werner syndrome (Maezawa et al., ; Yokote et al., ). These cases were operationally classified as examples of “Atypical Werner Syndrome.” Subsequent studies of the responsible mutations revealed that, with a single exception (pedigrees with a novel Peruvian type 2 Berardinelli–Seip syndrome) (Purizaca‐Rosillo et al., ), all highlighted major roles for DNA damage repair and response pathway genes, including LMNA (nuclear structure and chromatin interaction) (Chen et al., ), POLD1 (DNA polymerase delta) (Lessel et al., ), SPRTN (Lessel, Vaz, et al., ), ERCC4 (nucleotide excision repair) (Mori et al., ), MDM2 (major inhibitor of p53) (Lessel et al., ), SAMHD1 (regulation of dNTP pools) (Lessel, Saha et al., ), and CTC1 . The present study further supports the concept of genomic instability as a major mechanism of accelerated aging.…”

Section: Discussionmentioning

confidence: 99%

“…These cases were operationally classified as examples of "Atypical Werner Syndrome." Subsequent studies of the responsible mutations revealed that, with a single exception (pedigrees with a novel Peruvian type 2 Berardinelli-Seip syndrome) (Purizaca-Rosillo et al, 2017), all highlighted major roles for DNA damage repair and response pathway genes, including LMNA (nuclear structure and chromatin interaction) (Chen et al, 2003), POLD1 (DNA polymerase delta) (Lessel et al, 2015), SPRTN (Lessel, Vaz, et al, 2014), ERCC4 (nucleotide excision repair) (Mori et al, 2018), MDM2 (major inhibitor of p53) (Lessel et al, 2017), SAMHD1 (regulation of dNTP pools) (Lessel, Saha et al, 2014), and CTC1. The present study further supports the concept of genomic instability as a major mechanism of accelerated aging.…”

Section: Discussionmentioning

confidence: 99%

CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures

Sargolzaeiaval

Zhang

Schleit

et al. 2018

Molec Gen & Gen Med

Self Cite

View full text Add to dashboard Cite

BackgroundCerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication.MethodsA Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes.ResultsWhole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non‐telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC‐rich sequences.Conclusion CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra‐familial variations of CRMCC.

show abstract

“…Dysfunction of the MDM2‐p53 pathway has recently been linked to premature aging (PA) (Table ) . Lessel et al have reported the presence of an MDM2 mutation that results in the loss of MDM2 activity and p53 stabilization in a patient with segmental progeroid syndrome. This MDM2 mutant cannot rescue p53‐induced apoptosis in a zebrafish model, indicating that it is dysfunctional …”

Section: Roles Of Mdm2 In Other Noncancer Diseases and Conditionsmentioning

confidence: 99%

Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang

Qin

Rajaei

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the bestdocumented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases,

show abstract

Dysfunction of the MDM2/p53 axis is linked to premature aging

Cited by 60 publications

References 61 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures

Targeting MDM2 for novel molecular therapy: Beyond oncology

Contact Info

Product

Resources

About