The Double Life of the Ku Protein: Facing the DNA Breaks and the Extracellular Environment

Müller, Cathérine; Paupert, Jenny; Monferran, Sylvie; Salles, Bernard

doi:10.4161/cc.4.3.1565

Cited by 64 publications

(65 citation statements)

References 24 publications

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“…Observations through various experimental models indicate that Ku may act as either a tumor suppressor or an oncoprotein. Although they are predominantly nuclear proteins and primarily can be found in the transcriptionally active regions of the nucleus, recent studies showed that Ku proteins are also expressed in the cytoplasm, on the cell surface, and in the extracellular matrix (47,48). Ku is a component of the DNA-PK complex in membrane rafts of mammalian cells (49) and its membrane expression can be induced at hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Bednarek

Boncela

Smolarczyk

et al. 2008

Journal of Biological Chemistry

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Our data demonstrate that increased intracellular expression of thymosin ␤4 (T␤4) is necessary and sufficient to induce plasminogen activator inhibitor type 1 (PAI-1) gene expression in endothelial cells. To describe the mechanism of this effect, we produced T␤4 mutants with impaired functional motifs and tested their intracellular location and activity. Cytoplasmic distributions of T␤4 (AcSDKPT/4A) , T␤4 (KLKKTET/7A) , and T␤4 (K16A) mutants fused with green fluorescent protein did not differ significantly from those of wild-type T␤4. Overexpression of T␤4, T␤4 (AcSDKPT/4A) , and T␤4 (K16A) affected intracellular formation of actin filaments. As expected, T␤4 (K16A) uptake by nuclei was impaired. On the other hand, overexpression of T␤4 (KLKKTET/7A) resulted in developing the actin filament network typical of adhering cells, indicating that the mutant lacked the actin binding site. The mechanism by which intracellular T␤4 induced the PAI-1 gene did not depend upon the N-terminal tetrapeptide AcSDKP and depended only partially on its ability to bind G-actin or enter the nucleus. Both T␤4 and T␤4 (AcSDKPT/4A) induced the PAI-1 gene to the same extent, whereas mutants T␤4 (KLKKTET/7A) and T␤4 (K16A) retained about 60% of the original activity. By proteomic analysis, the Ku80 subunit of ATPdependent DNA helicase II was found to be associated with T␤4. Ku80 and T␤4 consistently co-immunoprecipitated in a complex from endothelial cells. Co-transfection of endothelial cells with the Ku80 deletion mutants and T␤4 showed that the C-terminal arm domain of Ku80 is directly involved in this interaction. Furthermore, down-regulation of Ku80 by specific short interference RNA resulted in dramatic reduction in PAI-1 expression at the level of both mRNA and protein synthesis. These data suggest that Ku80 functions as a novel receptor for T␤4 and mediates its intracellular activity.2 is the most abundant member of the highly conserved family of acidic polypeptides called ␤-thymosins. Although it is a typical intracellular polypeptide, it plays numerous roles, both intracellularly and extracellularly. Numerous observations indicate that T␤4 is involved in adhesion and spreading of fibroblasts (1, 2), differentiation of endothelial cells (3, 4), directional migration of endothelial cells and keratinocytes (5-8), angiogenesis (3-6, 9, 10), wound healing (6, 7, 11), hair follicle growth (8), and apoptosis (12, 13), and has been described to possess anti-inflammatory properties (11,14). In addition, elevated T␤4 expression has been observed in various malignant cell lines and tumors (15-17) and its levels seem to be associated with increased tumorigenicity and metastatic potential (10, 13, 18 -20). The increased expression of T␤4 correlates with the invasive capability of the cells, the degree of morphologic transformation, and disintegration of actin filaments (21). Recent studies have also correlated increased T␤4 expression with potentiated cell growth (13, 22) but this observation seems not to be universal (2, 10).T␤4 is conside...

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Section: Discussionmentioning

confidence: 99%

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Bednarek

Boncela

Smolarczyk

et al. 2008

Journal of Biological Chemistry

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“…Besides NHEJ, induction of Ku70 and Ku80 also leads to their translocation and involvement with Bax protein to trigger the apoptotic pathway (Muller et al, 2005). Thus, one can speculate that in addition to DNA damage, Vpr may use Ku family members to trigger the mitochondrial apoptotic pathway.…”

Section: Discussionmentioning

confidence: 99%

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

et al. 2007

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“…Ku is a heterodimeric protein composed of two subunits, Ku70 and Ku80; it was originally identified as an auto-antigen recognised by the sera of patients with autoimmune disease [25]. It is normally found in the nucleus where it plays a key role in non-homologous end joining (NHEJ), a major pathway in DSB repairs in humans [26]. Ku70/Ku80 is a key mediator in NHEJ and has been implicated in the radiosensitivity of a number of cancer types including the bladder, lung, breast, glioma, prostate, head and neck and cervix [27][28][29][30][31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

7B7: a novel antibody directed against the Ku70/Ku80 heterodimer blocks invasion in pancreatic and lung cancer cells

et al. 2014

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Development of more effective therapeutic strategies for cancers of high unmet need requires the continued discovery of disease-specific protein targets for therapeutic antibody targeting. In order to identify novel proteins associated with cancer cell invasion/metastasis, we present here an alternative to antibody targeting of cell surface proteins with an established role in invasion; our functional antibody screening approach involves the isolation and selection of

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The Double Life of the Ku Protein: Facing the DNA Breaks and the Extracellular Environment

Cited by 64 publications

References 24 publications

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

7B7: a novel antibody directed against the Ku70/Ku80 heterodimer blocks invasion in pancreatic and lung cancer cells

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