scholarly journals The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

Cell Reports ◽  
2014 ◽  
Vol 8 (3) ◽  
pp. 807-817 ◽  
Author(s):  
Andy Castillo ◽  
Atanu Paul ◽  
Baohua Sun ◽  
Ting Hsiang Huang ◽  
Yucai Wang ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Genomic Stability ◽  
Interacting Protein

scholarly journals ATRIP protects progenitor cells against DNA damage in vivo

2020 ◽  
Author(s):  
Gabriel E. Matos-Rodrigues ◽  
Paulius Grigaravicius ◽  
Bernard S. Lopez ◽  
Thomas Hofmann ◽  
Pierre-Olivier Frappart ◽  
...  
Keyword(s):  
Dna Damage ◽  
Progenitor Cells ◽  
Genome Stability ◽  
Genomic Stability ◽  
Interacting Protein ◽  
Replicative Stress ◽  
Dependent Cell ◽  
Short Life Expectancy

AbstractThe maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication.

scholarly journals ATRIP protects progenitor cells against DNA damage in vivo

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Gabriel E. Matos-Rodrigues ◽  
Paulius Grigaravicius ◽  
Bernard S. Lopez ◽  
Thomas G. Hofmann ◽  
Pierre-Olivier Frappart ◽  
...  
Keyword(s):  
Dna Damage ◽  
Progenitor Cells ◽  
Genome Stability ◽  
Genomic Stability ◽  
Interacting Protein ◽  
Replicative Stress ◽  
Dependent Cell ◽  
Short Life Expectancy

AbstractThe maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis, but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication.

scholarly journals Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiangbing Meng ◽  
Jason Z. Gao ◽  
Sean Michael T. Gomendoza ◽  
John W. Li ◽  
Shujie Yang
Keyword(s):  
Cancer Progression ◽  
Tumor Suppression ◽  
Tumor Suppressor Genes ◽  
Mevalonate Pathway ◽  
Genomic Stability ◽  
Mitotic Catastrophe ◽  
P53 Mutations ◽  
Aberrant Expression ◽  
Induce Cell Death ◽  
Recent Advances

p53 is among the most frequently mutated tumor suppressor genes given its prevalence in >50% of all human cancers. One critical tumor suppression function of p53 is to regulate transcription of downstream genes and maintain genomic stability by inducing the G1/S checkpoint in response to DNA damage. Tumor cells lacking functional p53 are defective in the G1/S checkpoint and become highly dependent on the G2/M checkpoint to maintain genomic stability and are consequently vulnerable to Wee1 inhibitors, which override the cell cycle G2/M checkpoint and induce cell death through mitotic catastrophe. In addition to the lost tumor suppression function, many mutated p53 (Mutp53) proteins acquire gain-of-function (GOF) activities as oncogenes to promote cancer progression, which manifest through aberrant expression of p53. In cancer cells with GOF Mutp53, statins can induce CHIP-mediated degradation of Mutp53 within the mevalonate pathway by blocking the interaction between mutp53 and DNAJA1. Therefore, targeting critical downstream pathways of Mutp53 provides an alternative strategy for treating cancers expressing Mutp53. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations.

The common fragile site FRA16D gene product WWOX: roles in tumor suppression and genomic stability

2014 ◽  
Vol 71 (23) ◽  
pp. 4589-4599 ◽  
Author(s):  
Rami I. Aqeilan ◽  
Muhannad Abu-Remaileh ◽  
Mohammad Abu-Odeh
Keyword(s):  
Gene Product ◽  
Tumor Suppression ◽  
Fragile Site ◽  
Genomic Stability ◽  
Common Fragile Site ◽  
The Common

scholarly journals Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia

2012 ◽  
Vol 196 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Jason Howitt ◽  
Jenny Lackovic ◽  
Ley-Hian Low ◽  
Adam Naguib ◽  
Alison Macintyre ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Tumor Suppression ◽  
Negative Regulator ◽  
Nuclear Entry ◽  
Interacting Protein ◽  
Akt Activation ◽  
Phosphorylated Akt ◽  
Phosphatase And Tensin Homologue

PTEN (phosphatase and tensin homologue deleted on chromosome TEN) is the major negative regulator of phosphatidylinositol 3-kinase signaling and has cell-specific functions including tumor suppression. Nuclear localization of PTEN is vital for tumor suppression; however, outside of cancer, the molecular and physiological events driving PTEN nuclear entry are unknown. In this paper, we demonstrate that cytoplasmic Pten was translocated into the nuclei of neurons after cerebral ischemia in mice. Critically, this transport event was dependent on a surge in the Nedd4 family–interacting protein 1 (Ndfip1), as neurons in Ndfip1-deficient mice failed to import Pten. Ndfip1 binds to Pten, resulting in enhanced ubiquitination by Nedd4 E3 ubiquitin ligases. In vitro, Ndfip1 overexpression increased the rate of Pten nuclear import detected by photobleaching experiments, whereas Ndfip1−/− fibroblasts showed negligible transport rates. In vivo, Ndfip1 mutant mice suffered larger infarct sizes associated with suppressed phosphorylated Akt activation. Our findings provide the first physiological example of when and why transient shuttling of nuclear Pten occurs and how this process is critical for neuron survival.

scholarly journals The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression

Oncogene ◽  
2009 ◽  
Vol 29 (1) ◽  
pp. 1-10 ◽  
Author(s):  
R Wäsch ◽  
J A Robbins ◽  
F R Cross
Keyword(s):  
Tumor Suppression ◽  
Genomic Stability

Early signalling events of autophagy

2013 ◽  
Vol 55 ◽  
pp. 1-15 ◽  
Author(s):  
Laura E. Gallagher ◽  
Edmond Y.W. Chan
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Interacting Protein ◽  
The Core ◽  
Autophagy Gene ◽  
Autophagy Induction ◽  
Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

Functional amyloid: widespread in Nature, diverse in purpose

2014 ◽  
Vol 56 ◽  
pp. 207-219 ◽  
Author(s):  
Chi L.L. Pham ◽  
Ann H. Kwan ◽  
Margaret Sunde
Keyword(s):  
Spider Silk ◽  
Epigenetic Inheritance ◽  
Fibrillar Structure ◽  
Cytoplasmic Polyadenylation ◽  
Functional Amyloid ◽  
Interacting Protein ◽  
Diverse Range ◽  
Element Binding Protein ◽  
Functional Amyloids ◽  
Micro Organisms

Amyloids are insoluble fibrillar protein deposits with an underlying cross-β structure initially discovered in the context of human diseases. However, it is now clear that the same fibrillar structure is used by many organisms, from bacteria to humans, in order to achieve a diverse range of biological functions. These functions include structure and protection (e.g. curli and chorion proteins, and insect and spider silk proteins), aiding interface transitions and cell–cell recognition (e.g. chaplins, rodlins and hydrophobins), protein control and storage (e.g. Microcin E492, modulins and PMEL), and epigenetic inheritance and memory [e.g. Sup35, Ure2p, HET-s and CPEB (cytoplasmic polyadenylation element-binding protein)]. As more examples of functional amyloid come to light, the list of roles associated with functional amyloids has continued to expand. More recently, amyloids have also been implicated in signal transduction [e.g. RIP1/RIP3 (receptor-interacting protein)] and perhaps in host defence [e.g. aDrs (anionic dermaseptin) peptide]. The present chapter discusses in detail functional amyloids that are used in Nature by micro-organisms, non-mammalian animals and mammals, including the biological roles that they play, their molecular composition and how they assemble, as well as the coping strategies that organisms have evolved to avoid the potential toxicity of functional amyloid.

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