scholarly journals Disruption of the Pdcd4 tumor suppressor gene in chicken DT40 cells reveals its role in the DNA-damage response

Oncogene ◽  
2009 ◽  
Vol 28 (42) ◽  
pp. 3758-3764 ◽  
Author(s):  
P Singh ◽  
R Marikkannu ◽  
N Bitomsky ◽  
K -H Klempnauer
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Dna Damage Response ◽  
Suppressor Gene ◽  
Damage Response ◽  
Dt40 Cells

scholarly journals Hops/Tmub1 Heterozygous Mouse Shows Haploinsufficiency Effect in Influencing p53-Mediated Apoptosis

2021 ◽  
Vol 22 (13) ◽  
pp. 7186
Author(s):  
Simona Ferracchiato ◽  
Nicola Di-Iacovo ◽  
Damiano Scopetti ◽  
Danilo Piobbico ◽  
Marilena Castelli ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Stress Responses ◽  
Mammalian Cells ◽  
P53 Protein ◽  
Suppressor Gene ◽  
Mrna Levels ◽  
Damage Response ◽  
Transcript Profiles

HOPS is a ubiquitin-like protein implicated in many aspects of cellular function including the regulation of mitotic activity, proliferation, and cellular stress responses. In this study, we focused on the complex relationship between HOPS and the tumor suppressor p53, investigating both transcriptional and non-transcriptional p53 responses. Here, we demonstrated that Hops heterozygous mice and mouse embryonic fibroblasts exhibit an impaired DNA-damage response to etoposide-induced double-strand breaks when compared to wild-type genes. Specifically, alterations in HOPS levels caused significant defects in the induction of apoptosis, including a reduction in p53 protein level and percentage of apoptotic cells. We also analyzed the effect of reduced HOPS levels on the DNA-damage response by examining the transcript profiles of p53-dependent genes, showing a suggestive deregulation of the mRNA levels for a number of p53-dependent genes. Taken together, these results show an interesting haploinsufficiency effect mediated by Hops monoallelic deletion, which appears to be enough to destabilize the p53 protein and its functions. Finally, these data indicate a novel role for Hops as a tumor-suppressor gene in DNA damage repair in mammalian cells.

scholarly journals PML Colocalizes with and Stabilizes the DNA Damage Response Protein TopBP1

2003 ◽  
Vol 23 (12) ◽  
pp. 4247-4256 ◽  
Author(s):  
Zhi-Xiang Xu ◽  
Anna Timanova-Atanasova ◽  
Rui-Xun Zhao ◽  
Kun-Sang Chang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Growth Regulation ◽  
Suppressor Gene ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Multifunctional Protein ◽  
Damage Response

ABSTRACT The PML tumor suppressor gene is consistently disrupted by t(15;17) in patients with acute promyelocytic leukemia. Promyelocytic leukemia protein (PML) is a multifunctional protein that plays essential roles in cell growth regulation, apoptosis, transcriptional regulation, and genome stability. Our study here shows that PML colocalizes and associates in vivo with the DNA damage response protein TopBP1 in response to ionizing radiation (IR). Both PML and TopBP1 colocalized with the IR-induced bromodeoxyuridine single-stranded DNA foci. PML and TopBP1 also colocalized with Rad50, Brca1, ATM, Rad9, and BLM. IR and interferon (IFN) coinduce the expression levels of both TopBP1 and PML. In PML-deficient NB4 cells, TopBP1 was unable to form IR-induced foci. All-trans-retinoic acid induced reorganization of the PML nuclear body (NB) and reappearance of the IR-induced TopBP1 foci. Inhibition of PML expression by siRNA is associated with a significant decreased in TopBP1 expression. Furthermore, PML-deficient cells express a low level of TopBP1, and its expression cannot be induced by IR or IFN. Adenovirus-mediated overexpression of PML in PML−/− mouse embryo fibroblasts substantially increased TopBP1 expression, which colocalized with the PML NBs. These studies demonstrated a mechanism of PML-dependent expression of TopBP1. PML overexpression induced TopBP1 protein but not the mRNA expression. Pulse-chase labeling analysis demonstrated that PML overexpression stabilized the TopBP1 protein, suggesting that PML plays a role in regulating the stability of TopBP1 in response to IR. Together, our findings demonstrate that PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage.

scholarly journals Normal ABL1 Is a Tumor Suppressor and Therapeutic Target In BCR-ABL1–positive Leukemias

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1466-1466
Author(s):  
Yashodhara Dasgupta ◽  
Mateusz Koptyra ◽  
Margaret Nieborowska-Skorska ◽  
Elisabeth Bolton Gillespie ◽  
Tomasz Stoklosa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Chromosome 9 ◽  
Myeloid Differentiation ◽  
Damage Response ◽  
Kinase Expression ◽  
Stimulation Of

Abstract BCR-ABL1 results from t(9;22)(q34;q11) reciprocal translocation resulting in BCR-ABL1 kinase expression, initiating chronic myeloid leukemia in chronic phase (CML-CP). At the initial stages of CML-CP both oncogenic BCR-ABL1 kinase and normal ABL1 kinase are expressed, however, loss of ABL1 kinase expression in CML-CP can result from an interstitial deletion in the normal chromosome 9 [del(9q34)] which may be combined with the transcriptional silencing of the alternative ABL1 promoter within the translocation eventually leading to disease progression and drug resistance. We found that BCR-ABL1 Abl1-/- cells generated a CML-blast phase (BP)-like disease phenotype in SCID mice compared to CML-CP-like disease from BCR-ABL1 Abl1+/+ cells. To determine the mechanisms responsible for blastic transformation of BCR-ABL1 Abl1-/- cells, we examined the role of ABL1 in proliferation, differentiation, apoptosis, genomic instability, and stemness. The presence of ABL1 inhibited proliferation in BCR-ABL1 cells as BCR-ABL1 Abl1-/- cells had higher clonogenic activity and proliferative rate compared to their wild-type counterparts. ABL1 is essential for myeloid differentiation since BCR-ABL1 Abl1-/- cells showed an immature blast phenotype when stained with Wright-Giemsa and myeloid differentiation markers Gr-1 and CD11b. ABL1 promoted apoptosis in response to genotoxic stress as revealed by reduced clonogenicity and elevated expression of p53, phosphoserine-15 p53 and activated caspase 3 in BCR-ABL1 Abl1 +/+ compared to knock-out cells. Although the absence of ABL1 did not enhance ROS and oxidative DNA damage, it appears that an impaired DNA damage response may be responsible for higher chromosome numbers and an accumulation of high numbers of chromosomal aberrations in BCR-ABL1 Abl1-/- cells. We detected an expansion of Lin-c-Kit+Sca-1+ leukemia stem cells (LSCs) in BCR-ABL1 Abl1-/- cells compared to BCR-ABL1 Abl1+/+ or non-transformed counterparts; among the LSCs, there was a higher percentage of CD34-Flt3- long-term and CD34+Flt3-short-term stem cells. These results showed that ABL1 is involved in regulating the LSC compartment in BCR-ABL1 cells. DNA microarray analysis revealed changes in mRNA levels of several genes involved in proliferation, myeloid differentiation, apoptosis, DNA damage response and stemness in BCR-ABL1 Abl1-/- cells in comparison to BCR-ABL1 Abl1+/+ cells. Together, these results demonstrated a critical role of ABL1 in BCR-ABL1-induced leukemia, prolonging survival in mice by suppressing proliferation and expansion of LSC, inducing myeloid differentiation, apoptosis and DNA damage response in BCR-ABL1 cells. Thus, it appears that ABL1 acts as a tumor suppressor in BCR-ABL1 –positive CML cells. Moreover, we hypothesized that the enhancement of the tumor suppressor function of ABL1 may have a significant impact on CML treatment. A small molecule activator of ABL1 kinase, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin (DPH), had been reported to interact with the myristoyl-binding site of ABL1 and destabilize the bent conformation of the α-1 helix, thereby preventing the auto-inhibitory conformation. DPH partially restored ABL1 activity in imatinib-treated cells. DPH-mediated stimulation of ABL1 tumor suppressor activity enhanced the effect of imatinib and ponatinib against CML CD34+ cells, Philadelphia chromosome-positive B-ALL (Ph+B-ALL) cells and relapsed Ph+B-ALL cells harboring T315I mutation without affecting normal counterparts. In summary, ABL1 is a potential tumor suppressor in BCR-ABL1-induced leukemia and stimulation of its function may play a significant role in the development of novel therapeutic strategies for CML and Ph+ALL. Disclosures: No relevant conflicts of interest to declare.

Inhibitory role of E2F-1 in the regulation of tumor suppressor p53 during DNA damage response

2012 ◽  
Vol 421 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Yukari Yoshihara ◽  
Dan Wu ◽  
Natsumi Kubo ◽  
Meixiang Sang ◽  
Akira Nakagawara ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Tumor Suppressor P53 ◽  
Inhibitory Role ◽  
Damage Response

scholarly journals Tumor suppressor NPRL2 induces ROS production and DNA damage response

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yinxing Ma ◽  
Licia Silveri ◽  
John LaCava ◽  
Svetlana Dokudovskaya
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Ros Production ◽  
Damage Response
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