Down-Regulation of Ku Autoantigen, DNA-Dependent Protein Kinase, and Poly(ADP-ribose) Polymerase during Cellular Senescence

Salminen, Antero; Helenius, Merja; Lahtinen, Tomi; Korhonen, Pauliina; Tapiola, Tero; Soininen, Hilkka; Solovyan, V. T.

doi:10.1006/bbrc.1997.7371

Cited by 31 publications

(24 citation statements)

References 24 publications

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“…It is important to note that animals enlisted in this study were chosen on the basis of chronological age rather than physiological decline, and none of the mice included in the analysis exhibited dermatitis, wounding or any signs of clinical infection. Together, these findings support the view that dysfunctional telomeres, perhaps coupled with age-dependent changes in innate immunity (Salminen et al, 1997;Um et al, 2003), leads to deregulated cytokine levels and a proinflammatory environment.…”

Section: Resultssupporting

confidence: 76%

“…Additionally, evidence has suggested possible role for DNA-PKcs in innate immunity, perhaps serving to modulate the response to immunostimulatory DNA and viral infection and engagement of downstream targets that activate cytokine cascades (Chu et al, 2000;Karpova et al, 2002). In the context of this report, it is also worth noting that an emerging literature has pointed to a decline in DNA-PKcs activity in aging tissues and in senescent cultured cells (Salminen et al, 1997;Um et al, 2003).…”

Section: Introductionmentioning

confidence: 71%

“…Indeed, TNFa (and other serum cytokine) levels correlate directly with age in the wild-type mouse (as seen by others; (Daynes et al, 1993;Ershler et al, 1993) and with telomere dysfunction in the telomerase mutant mouse ( Figure 5). In addition to diminished telomere reserves, DNA-PKcs function and DNA damage repair process also seem to decline with age either directly (Salminen et al, 1997;Um et al, 2003) or as a consequence of telomere dysfunction (Salminen et al, 1997;Um et al, 2003;Wong et al, 2000). Telomere shortening, ineffective DNA damage repair, deregulated cytokine cascade and ineffective immune system are all hallmarks of cellular and organismal aging.…”

Section: Discussionmentioning

confidence: 99%

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Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres

et al. 2006

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An adequate and appropriate response to physiological and pathophysiological stresses is critical for long-term homeostasis and viability of the aging organism. Previous work has pointed to the immune system, telomeres and DNA repair pathways as important and distinct determinants of a normal healthy lifespan. In this study, we explored the genetic interactions of telomeres and DNAPKcs, a protein involved in non-homologous end-joining (NHEJ) and immune responses, in the context of a key aspect of aging and lifespan -the capacity to mount an acute and appropriate immune-mediated stress response. We observed that the combination of DNA-PKcs deficiency and telomere dysfunction resulted in a shortened lifespan that was reduced further following viral infection or experimental activation of the innate immune response. Analysis of the innate immune response in the DNA-PKcs-deficient mice with short dysfunctional telomeres revealed high basal serum levels of tumor necrosis factor a (TNFa) and hyper-active cytokine responses upon challenge with polyinosinic-polycytidylic acid (poly-IC). We further show that serum cytokine levels become elevated in telomere dysfunctional mice as a function of age. These results raise speculation that these genetic factors may contribute to misdirected immune responses of the aged under conditions of acute and chronic stress.

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Section: Resultssupporting

confidence: 76%

Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres

et al. 2006

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“…This phenomenon has been described previously in replicatively senescent fibroblasts. 99 Our inability to detect cleaved PARP fragments in U373 C3 in particular may relate to the small number of cells that are undergoing apoptosis compared to the large number of cells that continue to express the senescent cell phenotype.…”

Section: Discussionmentioning

confidence: 96%

Expression of p57KIP2 Potently Blocks the Growth of Human Astrocytomas and Induces Cell Senescence

Tsugu

Sakai

Dirks

et al. 2000

The American Journal of Pathology

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Astrocytic tumors frequently exhibit defects in the expression or activity of proteins that control cellcycle progression. Inhibition of kinase activity associated with cyclin/cyclin-dependent kinase co-complexes by cyclin-dependent kinase inhibitors is an important mechanism by which the effects of growth signals are down-regulated. We undertook the present study to determine the role of p57 KIP2 (p57) in human astrocytomas. We demonstrate here that whereas p57 is expressed in fetal brain tissue, specimens of astrocytomas of varying grade and permanent astrocytoma cell lines do not express p57, and do not contain mutations of the p57 gene by multiplex-heteroduplex analysis. However, the inducible expression of p57 in three well-characterized human astrocytoma cell lines (U343 MG-A, U87 MG, and U373 MG) using the tetracycline repressor system leads to a potent proliferative block in G 1 as determined by growth curve and flow cytometric analyses. After the induction of p57, retinoblastoma protein, p107, and E2F-1 levels diminish, and retinoblastoma protein is shifted to a hypophosphorylated form. Morphologically, p57-induced astrocytoma cells became large and flat with an expanded cytoplasm. The inducible expression of p57 leads to the accumulation of senescence-associated ␤-galactosidase marker within all astrocytoma cell lines such that ϳ75% of cells were positive at 1 week after induction. Induction of p57 in U373 astrocytoma cells generated a small population of cells (ϳ15%) that were nonviable, contained discrete nuclear fragments on The most common brain tumor is the astrocytoma accounting for ϳ65% of all primary brain tumors. The malignant astrocytoma has a very poor prognosis primarily because of its highly proliferative and invasive nature. As with other neoplasms with increased proliferative potential, malignant astrocytomas demonstrate dysregulation of various components of the cell cycle machinery. Altered expression of positive growth regulators such as growth factors, cyclins, and cyclin-dependent kinases (CDKs), or the loss of negative regulators, including cyclin-dependent kinase inhibitors (CKIs) and the retinoblastoma protein (pRB) have all been demonstrated in malignant astrocytomas. 1,2 The CDKs phosphorylate pRB to release cells from cell-cycle arrest. In contrast with CDKs, the CKIs inhibit cyclin-CDK complexes and transduce internal or external growth suppressive signals. Accordingly, all CKIs may be construed as candidate tumor suppressor genes.The CKIs are divided into two families, the INK4 and the CIP/KIP, which are defined on the basis of their structural homology and mechanism of action. The CIP/KIP family includes three structurally related members, p21 CIP1/WAF1 , 3,4 p27 KIP1 , 5,6 and a recently isolated and cloned third member, p57 KIP2 (p57). 7-10 These three CKIs share a common N-terminal domain for binding to and inhibiting the kinase activity of CDK-cyclin complexes. Mouse p57 consists of four structurally distinct domains, a CDK inhibitory domain, a proline-rich domain, an a...

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“…There are several possible explanations: (1) Since they immortalize with lower e ciencies than wild-type, it is possible that they only confer the immortal phenotype on a sub-population of cells in the heterogeneous REF population that already carry an appropriate predisposition to immortalization; (2) These amino terminal fragments may be able to induce cellular cooperating mutations; it has been suggested that cellular mutations are more likely to occur in early passage cells than in established clonal cell lines where the genome is more stable (Salminen et al, 1997); and (3) T antigen may inactivate p53 through mechanisms other than direct binding. T antigen has the ability to induce cellular changes that result in the stabilization of p53 in the absence of direct binding (Deppert et al, 1989;Tiemann and Deppert, 1994).…”

Section: Activities Dependent Upon the Amino Terminusmentioning

confidence: 99%

Different functions are required for initiation and maintenance of immortalization of rat embryo fibroblasts by SV40 large T antigen

et al. 1999

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We have used two di erent, but complementary assays to characterize functions of SV40 T antigen that are necessary for its ability to immortalize rat embryo ®broblasts. In accordance with previous work, we found that several functions were required. These include activities that map to the p53 binding domain and the amino terminal 176 amino acids which contain the J domain as well as the CR1 and CR2 domain required for binding and sequestering the RB family of pocket proteins. Moreover, we found that even though activities dependent only upon the amino terminus were su cient for immortalization they were unable to maintain it. This suggests that immortalization by these amino terminal functions requires either additional events or immortalization of a subset of cells within the heterogeneous rat embryo ®broblast population. We further found that an activity dependent upon amino acids 17 ± 27 which remove a portion of the CR1 domain and the predicted a-1 helix of the J domain was not necessary to maintain growth but was required for direct immortalization suggesting that at least one of the functions required initially was not required to maintain the immortal state. This represents the ®rst demonstration that some of the functions required for maintenance of the immortal state di er from those required for initiation of immortalization.

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Down-Regulation of Ku Autoantigen, DNA-Dependent Protein Kinase, and Poly(ADP-ribose) Polymerase during Cellular Senescence

Cited by 31 publications

References 24 publications

Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres

Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres

Expression of p57KIP2 Potently Blocks the Growth of Human Astrocytomas and Induces Cell Senescence

Different functions are required for initiation and maintenance of immortalization of rat embryo fibroblasts by SV40 large T antigen

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