5 results on '"Joshua S Wahlstrom"'
Search Results
2. Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor
- Author
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Xiaohong Yu, Abhineet Uppal, Ralph R. Weichselbaum, Megan E. McNerney, Bakhtiar Yamini, Ashley M. Nassiri, Giovanna M. Bernal, Joshua S. Wahlstrom, Kirk E. Cahill, Adam M. Schmitt, Kenan Onel, David J. Voce, Clayton D. Crawley, and Kevin P. White
- Subjects
Male ,Cancer Research ,Programmed cell death ,Heterozygote ,Myeloid ,Alkylation ,DNA damage ,Down-Regulation ,lymphoma ,Haploinsufficiency ,Biology ,Article ,NF-κB ,law.invention ,Mice ,Downregulation and upregulation ,law ,Radiation, Ionizing ,Genetics ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Cell Death ,Tumor Suppressor Proteins ,NF-kappa B p50 Subunit ,Heterozygote advantage ,Mice, Inbred C57BL ,DNA Alkylation ,medicine.anatomical_structure ,Hypoxanthine-guanine phosphoribosyltransferase ,Immunology ,Cancer research ,Suppressor ,Female ,tumor suppression - Abstract
NF-κB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-κB1 as being necessary for cytotoxicity in response to DNA alkylation damage. Given the importance of damage-induced cell death for the maintenance of genomic stability, we examined whether Nfkb1 acts as a tumor suppressor in the setting of alkylation damage. Hprt mutation analysis demonstrates that Nfkb1(-/-) cells accumulate more alkylator-induced, but not ionizing radiation (IR)-induced, mutations than similarly treated wild-type cells. Subsequent in vivo tumor induction studies reveal that following alkylator treatment, but not IR, Nfkb1(-/-) mice develop more lymphomas than similarly treated Nfkb1(+/+) animals. Heterozygous mice develop lymphomas at an intermediate rate and retain functional p50 in their tumors, indicating that Nfkb1 acts in a haploinsufficient manner. Analysis of human cancers, including therapy-related myeloid neoplasms, demonstrates that NFKB1 mRNA expression is downregulated compared with control samples in multiple hematological malignancies. These data indicate that Nfkb1 is a haploinsufficient, pathway-specific tumor suppressor that prevents the development of hematologic malignancy in the setting of alkylation damage.
- Published
- 2014
3. Loss of Nfkb1 leads to early onset aging
- Author
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Joshua S. Wahlstrom, Hua Liang, Ralph R. Weichselbaum, Peter Pytel, Bakhtiar Yamini, Kirk E. Cahill, Giovanna M. Bernal, Clayton D. Crawley, and Shijun Kang
- Subjects
medicine.medical_specialty ,Aging ,CNS gliosis ,P50 ,Time Factors ,Genotype ,Longevity ,Inflammation ,Apoptosis ,Biology ,Bone and Bones ,Histones ,Nfkb1 ,Internal medicine ,Gene expression ,medicine ,Animals ,Gliosis ,Kyphosis ,Phosphorylation ,γH2AX ,Cells, Cultured ,Cellular Senescence ,Mice, Knockout ,Wild type ,Age Factors ,Brain ,NF-kappa B p50 Subunit ,Aging, Premature ,Cell Biology ,DNA ,Fibroblasts ,NFKB1 ,Mice, Inbred C57BL ,Endocrinology ,Phenotype ,Immunology ,Replicative senescence ,medicine.symptom ,Cell aging ,Research Paper - Abstract
NF-κB is a major regulator of age-dependent gene expression and the p50/NF-κB1 subunit is an integral modulator of NF-κB signaling. Here, we examined Nfkb1-/- mice to investigate the relationship between this subunit and aging. Although Nfkb1-/- mice appear similar to littermates at six months of age, by 12 months they have a higher incidence of several observable age-related phenotypes. In addition, aged Nfkb1-/- animals have increased kyphosis, decreased cortical bone, increased brain GFAP staining and a decrease in overall lifespan compared to Nfkb1+/+. In vitro, serially passaged primary Nfkb1-/- MEFs have more senescent cells than comparable Nfkb1+/+ MEFs. Also, Nfkb1-/- MEFs have greater amounts of phospho-H2AX foci and lower levels of spontaneous apoptosis than Nfkb1+/+, findings that are mirrored in the brains of Nfkb1-/- animals compared to Nfkb1+/+. Finally, in wildtype animals a substantial decrease in p50 DNA binding is seen in aged tissue compared to young. Together, these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-κB pathway and mammalian aging.
- Published
- 2015
4. S-phase-dependent p50/NF-кB1 phosphorylation in response to ATR and replication stress acts to maintain genomic stability
- Author
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Bakhtiar Yamini, Clayton D. Crawley, Kirk E. Cahill, David R. Raleigh, Andrea Garofalo, Ralph R. Weichselbaum, Shijun Kang, Giovanna M. Bernal, David J. Voce, and Joshua S. Wahlstrom
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Genome instability ,p50 ,Bclxl ,Bcl-2-like protein ,Electrophoretic Mobility Shift Assay ,homologous recombination ,Ataxia Telangiectasia Mutated Proteins ,temozolomide ,inhibitor kappaB ,hydroxyurea ,NF-κB ,S Phase ,ataxia telangiectasia mutated ,histone 2AX ,chemistry.chemical_compound ,HR ,2.1 Biological and endogenous factors ,H2AX ,Phosphorylation ,Aetiology ,Luciferases ,Cancer ,double-strand breaks ,tamoxifen ,Reverse Transcriptase Polymerase Chain Reaction ,Cell biology ,nuclear factor-kappaB ,RNA Interference ,Comet Assay ,DSBs ,ionizing radiation ,DNA Replication ,DNA damage ,replication stress ,S-phase ,short interfering RNA ,1.1 Normal biological development and functioning ,Immunoblotting ,Chk1 ,ChIP ,RT-PCR ,inhibitor kappaB kinase ,chromatin immunoprecipitation ,Biology ,Real-Time Polymerase Chain Reaction ,IκB ,Genomic Instability ,BCL2-associated X protein ,RS ,Cell Cycle News & Views ,IκK ,Underpinning research ,Genetics ,Humans ,Immunoprecipitation ,ataxia telangiectasia mutated and Rad3-related ,CHEK1 ,Molecular Biology ,DNA Primers ,checkpoint kinase 1 ,Human Genome ,DNA replication ,NF-kappa B p50 Subunit ,TopBP1 ,Cell Biology ,G2-M DNA damage checkpoint ,Molecular biology ,ATR ,chemistry ,Hu ,TAM ,Bax ,ATM ,siRNA ,IR ,Biochemistry and Cell Biology ,TMZ ,topoisomerase-binding protein-1 ,DNA ,Developmental Biology - Abstract
The apical damage kinase, ATR, is activated by replication stress (RS) both in response to DNA damage and during normal S-phase. Loss of function studies indicates that ATR acts to stabilize replication forks, block cell cycle progression and promote replication restart. Although checkpoint failure and replication fork collapse can result in cell death, no direct cytotoxic pathway downstream of ATR has previously been described. Here, we show that ATR directly reduces survival by inducing phosphorylation of the p50 (NF-κB1, p105) subunit of NF-кB and moreover, that this response is necessary for genome maintenance independent of checkpoint activity. Cell free and in vivo studies demonstrate that RS induces phosphorylation of p50 in an ATR-dependent but DNA damage-independent manner that acts to modulate NF-кB activity without affecting p50/p65 nuclear translocation. This response, evident in human and murine cells, occurs not only in response to exogenous RS but also during the unperturbed S-phase. Functionally, the p50 response results in inhibition of anti-apoptotic gene expression that acts to sensitize cells to DNA strand breaks independent of damage repair. Ultimately, loss of this pathway causes genomic instability due to the accumulation of chromosomal breaks. Together, the data indicate that during S-phase ATR acts via p50 to ensure that cells with elevated levels of replication-associated DNA damage are eliminated.
- Published
- 2015
5. p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage
- Author
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Clayton D. Crawley, Adam M. Schmitt, Xiaohong Yu, Bakhtiar Yamini, Ralph R. Weichselbaum, Joshua S. Wahlstrom, David R. Raleigh, David J. Voce, Shijune Kang, and Thomas E. Darga
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Cell Death ,DNA damage ,Effector ,Mutant ,NF-kappa B p50 Subunit ,Cell Biology ,Biology ,DNA Methylation ,Molecular biology ,Article ,Mice ,Cell Line, Tumor ,DNA methylation ,Gene expression ,Phosphorylation ,Cytotoxic T cell ,Animals ,Humans ,Signal transduction ,Molecular Biology ,DNA Damage - Abstract
The functional significance of the signaling pathway induced by O(6)-methylguanine (O(6)-MeG) lesions is poorly understood. Here, we identify the p50 subunit of NF-κB as a central target in the response to O(6)-MeG and demonstrate that p50 is required for S(N)1-methylator-induced cytotoxicity. In response to S(N)1-methylation, p50 facilitates the inhibition of NF-κB-regulated antiapoptotic gene expression. Inhibition of NF-κB activity is noted to be an S phase-specific phenomenon that requires the formation of O(6)-MeG:T mismatches. Chk1 associates with p50 following S(N)1-methylation, and phosphorylation of p50 by Chk1 results in the inhibition of NF-κB DNA binding. Expression of an unphosphorylatable p50 mutant blocks inhibition of NF-κB-regulated antiapoptotic gene expression and attenuates S(N)1-methylator-induced cytotoxicity. While O(6)-MeG:T-induced, p50-dependent signaling is not sufficient to induce cell death, this pathway sensitizes cells to the cytotoxic effects of DNA breaks.
- Published
- 2011
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