Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death

Yang, Chuanchuan; Leskov, Konstantin; Hosley-Eberlein, Kelly; Criswell, Tracy; Pink, John J.; Kinsella, Timothy J.; Boothman, David A.

doi:10.1073/pnas.97.11.5907

Cited by 272 publications

(330 citation statements)

References 27 publications

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“…16 nCLU, but not sCLU, protein binds to Ku70, forming a trimeric protein complex with Ku80; Ku70 and Ku80 are two components of the DNA-PK complex, involved in nonhomologous DNA DSB repair. 16,24 DNA-PK is a nuclear serine/threonine kinase that requires DNA ends for catalytic activity. It is selectively activated by binding to the ends of linear doublestrand DNA.…”

Section: Clu and Dna Repairmentioning

confidence: 99%

“…16 Recent data by our group indicate that Ku70 plays an important dual role in binding Bax and protecting cells from Bax-mediated cell death responses. 24,26 We are currently testing the hypothesis that nCLU acts to release Bax from the cytoprotective Ku70-Bax complex, as well as prevent nonhomologous end joining through the inhibition of Ku70-Ku80 end binding activity. 26 …”

Section: Clu and Dna Repairmentioning

confidence: 99%

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Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

et al. 2005

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Clusterin (CLU) has been implicated in various cell functions involved in carcinogenesis and tumour progression. There are two known CLU protein isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is proapoptotic, and a secretory form (sCLU) is prosurvival. CLU expression has been associated with tumorigenesis of various malignancies, including tumours of prostate, colon, and breast. Furthermore, CLU expression is modulated by many factors that are believed to regulate tumour growth and/or apoptosis, including 1,25-dihydroxyvitamin D 3 , transforming growth factor beta-1, ultraviolet radiation, and IR. sCLU upregulation appears to be a general molecular stress response. Presently, preliminary results indicate that therapeutic modalities targeting CLU may be effective in cancer treatment. However, such strategies should make sure that nCLU is not eliminated or reduced. This review summarizes our present understanding of the importance of CLU in various physiological functions including tumour growth, and discusses its relevance to future cancer therapy.

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Section: Clu and Dna Repairmentioning

confidence: 99%

Section: Clu and Dna Repairmentioning

confidence: 99%

Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

et al. 2005

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“…In contrast, other groups have reported a lack of evidence for clusterin expression in apoptotic thymocytes [14], [15] while others have shown that, not apoptotic cells themselves but rather, bystander cells surviving the apoptotic process might be the source of clusterin production [16] [16]. In addition to these reports, contradictory observations on the role of clusterin in both protecting [17] and promoting apoptosis [18] have been reported; therefore the biological function of clusterin during apoptosis is indeed confusing and conflicting.…”

Section: Introductionmentioning

confidence: 95%

Clusterin mRNA expression in apoptotic and activated rat thymocytes

Park

et al. 2003

Cell Res

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Clusterin is a 75-80 kDa heterodimeric glycoprotein, that is produced in most tissues but which exact biological role is still not clear. Particularly, its role in protection or promotion of apoptosis is heavily disputed, since data supporting both views have been reported in several independent studies. To clarify this issue, and also to determine whether clusterin expression itself might be affected by apoptosis, in the present study, rat thymocytes were treated with dexamethasone, -a synthetic glucocorticoid that elicits apoptosis in thymocytes-, and clusterin mRNA expression was analyzed by semi-quantitative RT-PCR before and after induction of apoptosis. Interestingly, neither the treatment with dexamethasone in vitro nor triggering of apoptosis in vivo up-regulated clusterin expression, opposing the view that clusterin is involved in apoptotic processes. On the other hand, a new clusterin mRNA isoform was detected and isolated, whose expression was restricted to freshly isolated thymocytes. This novel isoform lacks the post-translational proteolytic cleavage site and is therefore predicted to encode a monomeric protein. The biological function under normal circumstances, however, will need further investigations for clarification. While apoptosis could not modulate clusterin expression, activation of thymocytes with concanavalin A and interleukin-2 resulted in up-regulation of clusterin mRNA level, indicating that clusterin expression is rather under the control of cell activation-mediated rather than apoptosis-induced signals.

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“…The secretory form of clusterin (sCLU) is synthesized as a 50-60 kDa protein precursor and targeted to the endoplasmic reticulum (ER) by a leader peptide that is 22 amino acids long [18]. Then the precursor is glycosylated and proteolytically cleaved into α and β subunits, held together by disulfide bonds [41,43]. Mature sCLU is secreted into body fluids as an ∼80 kDa heterodimeric glycoprotein containing a ∼40 kDa α and β protein subunit [43].…”

Section: Introductionmentioning

confidence: 99%

“…Then the precursor is glycosylated and proteolytically cleaved into α and β subunits, held together by disulfide bonds [41,43]. Mature sCLU is secreted into body fluids as an ∼80 kDa heterodimeric glycoprotein containing a ∼40 kDa α and β protein subunit [43]. sCLU has been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

Presence, localization, and origin of clusterin in normal human spermatozoa

Han

Wang

Cheng

et al. 2012

J Assist Reprod Genet

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Purpose Clusterin in mammalian semen is a secretory form of clusterin (sCLU) with the heterodimeric structure. It is secreted by the epididymis and seminal vesicle. It is generally agreed that clusterin mainly exists on the surface of abnormal spermatozoa and is implicated in decreased sperm motility, sperm aggregation and infertility. However, few studies observe clusterin in normal spermatozoa, which is presumed to be a novel form. Up to now, the systematical information about the presence, localization, origin and function of clusterin in normal human spermatozoa has yet not been established. The aim of our current study is to systematically research clusterin in normal human spermatozoa.Methods We detected the presence of clusterin via western blot, explored the localization of clusterin using immunofluorescence, and investigated the origin and distribution of clusterin in human testis by western blot and immunohistochemistry. Results We found native clusterin in the inner plasma membrane of normal human spermatozoa. It was derived from the testis and showed similar molecular weight and heterodimeric structure compared with sCLU in semen and on the surface of abnormal spermatozoa. Conclusion Clusterin in normal spermatozoa should be self-synthesized during the later stage of spermatogenesis. The different localization and origin suggested that the clusterin observed by us may be a novel form compared with conventional sCLU on the surface of abnormal spermatozoa.

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Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death

Cited by 272 publications

References 27 publications

Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

Clusterin mRNA expression in apoptotic and activated rat thymocytes

Presence, localization, and origin of clusterin in normal human spermatozoa

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