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https://www.readbyqxmd.com/read/29339502/protein-aggregation-of-the-p63-transcription-factor-underlies-severe-skin-fragility-in-aec-syndrome
#1
Claudia Russo, Christian Osterburg, Anna Sirico, Dario Antonini, Raffaele Ambrosio, Julia Maren Würz, Jörg Rinnenthal, Marco Ferniani, Sebastian Kehrloesser, Birgit Schäfer, Peter Güntert, Satrajit Sinha, Volker Dötsch, Caterina Missero
The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29339410/maintenance-of-genome-integrity%C3%A2-by-mi2-homologs-chd-3-and-let-418-in%C3%A2-caenorhabditis-elegans
#2
Carolyn A Turcotte, Solomon A Sloat, Julia A Rigothi, Erika Rosenkranse, Alexandra L Northrup, Nicolas P Andrews, Paula M Checchi
Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination...
January 16, 2018: Genetics
https://www.readbyqxmd.com/read/29335245/cdk9-mediated-phosphorylation-controls-the-interaction-of-tip60-with-the-transcriptional-machinery
#3
Prisca Brauns-Schubert, Florian Schubert, Manuela Wissler, Martina Weiss, Lisa Schlicher, Simon Bessler, Mariam Safavi, Cornelius Miething, Christoph Borner, Tilman Brummer, Ulrich Maurer
The acetyltransferase TIP60 is regulated by phosphorylation, and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53-mediated induction of the BCL-2 protein PUMA. TIP60 phosphorylation by GSK-3 requires a priming phosphorylation on S90, and here, we identify CDK9 as a TIP60S90 kinase. We demonstrate that a phosphorylation-deficient mutant, TIP60S90A, exhibits reduced interaction with chromatin, histone 3 and RNA Pol II, while its association with the TIP60 complex subunit EPC1 is not affected...
January 15, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29330147/genetic-ablation-of-rbm38-promotes-lymphomagenesis-in-the-context-of-mutant-p53-by-downregulating-pten
#4
Jin Zhang, Enshun Xu, Cong Ren, Hee Jung Yang, Yanhong Zhang, Wenqiang Sun, Xiangmudong Kong, Weici Zhang, Mingyi Chen, Eric C Huang, Xinbin Chen
Mutant p53 exerts gain-of-function effects that drive metastatic progression and therapeutic resistance, but the basis for these effects remain obscure. The RNA binding protein RBM38 limits translation of mutant p53 and is often ablated in tumors harboring it. Here we show how loss of Rbm38 significantly alters cancer susceptibility in mutant p53 knock-in mice, by shortening lifespan, altering tumor incidence and promoting T cell lymphomagenesis. Loss of Rbm38 enhanced mutant p53 expression and decreased expression of the tumor suppressor Pten, a key regulator of T cell development...
January 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29330109/friend-or-foe-micrornas-in-the-p53-network
#5
Zhenghua Luo, Ri Cui, Esmerina Tili, Carlo Croce
The critical tumor suppressor gene TP53 is either lost or mutated in more than half of human cancers. As an important transcriptional regulator, p53 modulates the expression of many microRNAs. While wild-type p53 uses microRNAs to suppress cancer development, microRNAs that are activated by gain-of-function mutant p53 confer oncogenic properties. On the other hand, the expression of p53 is tightly controlled by a fine-tune machinery including microRNAs. MicroRNAs can target the TP53 gene directly or other factors in the p53 network so that expression and function of either the wild-type or the mutant forms of p53 is downregulated...
January 9, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29321954/a-role-for-caspase-2-in-sphingosine-kinase-1-proteolysis-in-response-to-doxorubicin-in-breast-cancer-cells-implications-for-the-chk1-suppressed-pathway
#6
Brittany L Carroll, Joseph Bonica, Achraf A Shamseddine, Yusuf A Hannun, Lina M Obeid
Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA-damaging agents. Moreover, loss of SK1 in p53-knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53...
January 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29302887/analysis-of-immunobiologic-markers-in-primary-and-recurrent-glioblastoma
#7
Maryam Rahman, Jesse Kresak, Changlin Yang, Jianping Huang, Wesley Hiser, Paul Kubilis, Duane Mitchell
Glioblastoma (GBM) generates a varied immune response and understanding the immune microenvironment may lead to novel immunotherapy treatments modalities. The goal of this study was to evaluate the expression of immunologic markers of potential clinical significance in primary versus recurrent GBM and assess the relationship between these markers and molecular characteristics of GBM. Human GBM samples were evaluated and analyzed with immunohistochemistry for multiple immunobiologic markers (CD3, CD8, FoxP3, CD68, CD163, PD1, PDL1, CTLA4, CD70)...
January 4, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29301793/o-glcnacylation-of-the-tumor-suppressor-foxo3-triggers-aberrant-cancer-cell-growth
#8
Heon Shin, Hyun-Jeong Cha, Keun Na, Min Jung Lee, Jin-Young Cho, Chae-Yeon Kim, Eun Kyung Kim, Chang Moo Kang, Hoguen Kim, Young-Ki Paik
Post-translational modifications of tumor suppressors can induce abnormal cell growth. Here we identify site-specific O-GlcNAcylation as a critical block of FOXO3 that may abrogate a part of the p53 pathway, resulting in aberrant cancer cell growth. Of seven O-GlcNAcylation sites identified within the FOXO3 transactivation domain, we found that changes in O-GlcNAcylation at Ser284 modulated p21-mediated cancer cell growth. Overexpression of either O-GlcNAcylated FOXO3 (FOX-OV) or a Ser-to-Ala mutant (S284A) in PANC-1 cells indicated that S284 O-GlcNAc acts as a critical block of the FOXO tumor suppressor and induces proliferation in PANC-1 cancer cells by stimulating the MDM2-p53-p21 axis...
January 4, 2018: Cancer Research
https://www.readbyqxmd.com/read/29298839/dna-binding-by-the-mat%C3%AE-2-transcription-factor-controls-its-access-to-alternative-ubiquitin-modification-pathways
#9
Christopher M Hickey, Yang Xie, Mark Hochstrasser
Like many transcription factors, the yeast protein MATalpha2 (α2) undergoes rapid proteolysis via the ubiquitin-proteasome system (UPS). At least two ubiquitylation pathways regulate α2 degradation: one pathway utilizes the ubiquitin ligase (E3) Doa10 and the other the heterodimeric E3 Slx5/Slx8. Doa10 is a transmembrane protein of the endoplasmic reticulum/inner nuclear membrane, whereas Slx5/Slx8 localizes to the nucleus and binds DNA nonspecifically. While a single protein can often be ubiquitylated by multiple pathways, the reasons for this 'division of labor' are not well understood...
January 3, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29298430/monoclonal-antibodies-against-specific-p53-hotspot-mutants-as-potential-tools-for-precision-medicine
#10
Le-Ann Hwang, Beng Hooi Phang, Oi Wah Liew, Jabed Iqbal, Xiao Hui Koh, Xin Yu Koh, Rashidah Othman, Yuezhen Xue, A Mark Richards, David P Lane, Kanaga Sabapathy
The large number of mutations identified across all cancers represents an untapped reservoir of targets that can be useful for therapeutic targeting if highly selective, mutation-specific reagents are available. We report here our attempt to generate such reagents: monoclonal antibodies against the most common R175H, R248Q, and R273H hotspot mutants of the tumor suppressor p53. These antibodies recognize their intended specific alterations without any cross-reactivity against wild-type (WT) p53 or other p53 mutants, including at the same position (as exemplified by anti-R248Q antibody, which does not recognize the R248W mutation), evaluated by direct immunoblotting, immunoprecipitation, and immunofluorescence methods on transfected and endogenous proteins...
January 2, 2018: Cell Reports
https://www.readbyqxmd.com/read/29282022/chromosomal-instability-induced-by-increased-birc5-survivin-levels-affects-tumorigenicity-of-glioma-cells
#11
Marina Conde, Susanne Michen, Ralf Wiedemuth, Barbara Klink, Evelin Schröck, Gabriele Schackert, Achim Temme
BACKGROUND: Survivin, belonging to the inhibitor of apoptosis (IAP) gene family, is abundantly expressed in tumors. It has been hypothesized that Survivin facilitates carcinogenesis by inhibition of apoptosis resulting in improved survival of tumorigenic progeny. Additionally, Survivin plays an essential role during mitosis. Together with its molecular partners Aurora B, Borealin and inner centromere protein it secures bipolar chromosome segregation. However, whether increased Survivin levels contribute to progression of tumors by inducing chromosomal instability remains unclear...
December 28, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29280266/senescence-promotes-in%C3%A2-vivo-reprogramming-through-p16ink4a-and-il-6
#12
Lluc Mosteiro, Cristina Pantoja, Alba de Martino, Manuel Serrano
Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin-6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c-Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity. In this system, Ink4a/Arf-null tissues cannot undergo senescence, fail to produce IL6, and cannot reprogram efficiently; whereas p53-null tissues undergo extensive damage and senescence, produce high levels of IL6, and reprogram efficiently...
December 27, 2017: Aging Cell
https://www.readbyqxmd.com/read/29260852/targeting-the-prion-like-aggregation-of-mutant-p53-to-combat-cancer
#13
Jerson L Silva, Elio A Cino, Iaci N Soares, Vitor F Ferreira, Guilherme A P de Oliveira
Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties...
December 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29258181/prima-1-and-prima-1met-apr-246-from-mutant-wild-type-p53-reactivation-to-unexpected-mechanisms-underlying-their-potent-anti-tumor-effect-in-combinatorial-therapies
#14
REVIEW
Anne Perdrix, Ahmad Najem, Sven Saussez, Ahmad Awada, Fabrice Journe, Ghanem Ghanem, Mohammad Krayem
p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress...
December 16, 2017: Cancers
https://www.readbyqxmd.com/read/29247526/effects-of-shrna-mediated-silencing-of-psma7-on-cell-proliferation-and-vascular-endothelial-growth-factor-expression-via-the-ubiquitin-proteasome-pathway-in-cervical-cancer
#15
Chen-Chen Ren, Li Yang, Ling Liu, Yan-Nan Chen, Guo-Mei Cheng, Xiao-An Zhang, Hui Liu
This study aims to evaluate the effects of PSMA7 silencing on cervical cancer (CC) cell proliferation and vascular endothelial growth factor (VEGF) expression through the ubiquitin-proteasome (UPP) pathway. CC tissue (n = 43) and normal tissues (n = 27) were first collected from patients. Human CC cell line (SiHa) and human normal cervical epithelial cells (H8) were obtained and classified into the normal, blank, negative control (NC), PSMA7-shRNA1 and PSMA7-shRNA2 groups. Hybridization in situ was used to detect the expressions of wild-type and mutant p53 proteins...
December 16, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29245943/saikosaponin-d-a-calcium-mobilizing-agent-sensitizes-chemoresistant-ovarian-cancer-cells-to-cisplatin-induced-apoptosis-by-facilitating-mitochondrial-fission-and-g2-m-arrest
#16
Hideaki Tsuyoshi, Vincent Kam Wai Wong, Yu Han, Makoto Orisaka, Yoshio Yoshida, Benjamin K Tsang
Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29244835/tumor-suppressor-protein-p53-mediated-repression-of-human-mitotic-centromere-associated-kinesin-gene-expression-is-exerted-via-down-regulation-of-sp1-level
#17
Do Youn Jun, Ji Young Lee, Hae Sun Park, Yun Han Lee, Young Ho Kim
The repressive role of p53 on the human mitotic centromere-associated kinesin (MCAK) core promoter from ‒266 to +54, relative to the transcription start site, has been determined. The MCAK mRNA and protein levels were 2.1- and 3.0-fold higher, respectively, in HCT116 (p53‒/‒) than in HCT116 (p53+/+) cells. Enforced down-regulation of p53 levels either in HCT116 (p53+/+) cells by p53 RNAi treatment or in MCF-7 cells using shRNA for p53 (shp53) resulted in a remarkable increase in the MCAK protein level...
2017: PloS One
https://www.readbyqxmd.com/read/29242642/targeting-mutant-p53-for-efficient-cancer-therapy
#18
REVIEW
Vladimir J N Bykov, Sofi E Eriksson, Julie Bianchi, Klas G Wiman
The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials...
December 15, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29240881/nrf2-promotes-mutant-k-ras-p53-driven-pancreatic-carcinogenesis
#19
Shin Hamada, Keiko Taguchi, Atsushi Masamune, Masayuki Yamamoto, Tooru Shimosegawa
The Keap1-Nrf2 system contributes to the maintenance of homeostasis by regulating oxidative stress responses in normal tissues and organs, and is exploited in various cancers for proliferation, survival and acquisition of therapy resistance. Pancreatic cancer remains one of the intractable cancers, despite the improved clinical outcomes of other types of cancer, due to its invasive and refractory nature to therapeutic intervention. The current study aimed to clarify the contribution of Nrf2 to pancreatic carcinogenesis using a pancreas-specific mutant K-ras and p53 (KPC) mouse model...
June 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29239139/btg2-is-a-tumor-suppressor-gene-upregulated-by-p53-and-pten-in-human-bladder-carcinoma-cells
#20
Ke-Hung Tsui, Kun-Chun Chiang, Yu-Hsiang Lin, Kang-Shuo Chang, Tsui-Hsia Feng, Horng-Heng Juang
Although widely deemed as a tumor suppressor gene, the role of B-cell translocation gene 2 (BTG2) in bladder cancer is still inconclusive. We investigated the role and regulatory mechanism of BTG2 in bladder cancer. BTG2 expression in human bladder tissues was determined by RT-qPCR and immunoblotting assays. Expressions of BTG2 and PTEN in bladder carcinoma cells were determined by immunoblotting, RT-qPCR, or reporter assays. The 3 H-thymidine incorporation assay, flow cytometry, and the xenograft animal model were used to determine the cell growth...
December 13, 2017: Cancer Medicine
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