Clusterin proteins: stress-inducible polypeptides with proposed functions in multiple organ dysfunction

Araki, Shinako; Israel, Steffen; Leskov, Konstantin; Criswell, Tracy; Beman, Meghan; Klokov, Dmitry; Sampalth, L; Reinicke, Kathryn E.; Cataldo, Eva; Mayo, Lindsey D.; Boothman, David A.

doi:10.1259/bjr/18105113

Cited by 13 publications

(8 citation statements)

References 39 publications

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“…IGF-1-sCLU expression is hypersensitive to IR, as well as many other cytotoxic stresses, including elevated O 2 exposures and agents that do not damage DNA, but alter osmotic homeostasis (21). IGF-1-sCLU induction is long-lived and proportional to IR exposures between 10–100 cGy in vitro (Figure 1) and in vivo (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

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Low dose IR-induced IGF-1-sCLU expression: a p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect

et al. 2012

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Inadvertent mammalian tissue exposures to low doses of ionizing radiation (IR) after radiation accidents, remediation of radioactive-contaminated areas, space travel, or a dirty bomb represents an interesting trauma to an organism. Possible low dose IR-induced bystander effects could impact our evaluation of human health effects, since cells within tissue are not equally damaged after doses of IR ≤10 cGy. To understand tissue responses after low IR doses, we generated a reporter system using the human clusterin promoter fused to firefly luciferase (hCLUp-Luc). Secretory clusterin (sCLU), an extra-cellular molecular chaperone, induced by low doses of cytotoxic agents, clears cell debris. Low dose IR (≥2 cGy) exposure induced hCLUp-Luc activity with peak levels at 96 h, consistent with endogenous sCLU levels. As doses increased (≥1 Gy), sCLU induction amplitudes increased and time to peak response decreased. sCLU expression was stimulated by IGF-1, but suppressed by p53. Responses in transgenic hCLUp-Luc reporter mice after low IR doses showed that specific tissues (i.e., colon, spleen, mammary, thymus, bone marrow) of female mice induced hCLUp-Luc activity more than male mice after whole body (≥10 cGy) irradiation. Tissue-specific, non-linear dose- and time-responses of hCLUp-Luc and endogenous sCLU levels were noted. Colon maintained homeostatic balance after 10 cGy. Bone marrow responded with delayed, but prolonged and elevated expression. Intraperitoneal administration of α-TGFβ1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling via activated TGFβ1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGFβ1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGFβ1 signaling and promotes wound healing.

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Section: Discussionmentioning

confidence: 99%

“…Irradiated tissue responses may be responding to trauma by inducing IGF-1-sCLU for simultaneous wound healing and cell debris clearance to avoid multiple organ dysfunction (MOD) (21). However, formation of genetically unstable cells, or cells with long-lived memory of IR damage would tend to permanently up-regulate IGF-1-sCLU expression (1).…”

Section: Discussionmentioning

confidence: 99%

Low dose IR-induced IGF-1-sCLU expression: a p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect

et al. 2012

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“…In this report, we provide evidence that clusterin can be retrotranslocated from the secretory system to the cytosol through a mechanism similar to endoplasmic reticulum‐associated protein degradation (ERAD). The founder observation that led to this study is the paradoxical decrease of mature clusterin protein in situations of cellular stress where the clusterin gene is upregulated, such as treatment with thapsigargin (Tg) (21). This effect was also produced by a high extracellular concentration of KCl, which is known to induce stress gene expression in U251 astrocytic cells (22) and is naturally observed during ischemia, which itself is an inducer of clusterin expression (23).…”

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confidence: 94%

Stress‐Induced Retrotranslocation of Clusterin/ApoJ into the Cytosol

Nizard

Tetley

Dréan

et al. 2007

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Clusterin is a usually secreted glycoprotein with chaperone properties. Recently, it has been suggested that clusterin isoforms reside in the nuclear and cytosolic compartments of human cell types, where they can influence various cellular programs including DNA repair, transcription and apoptosis. Several mechanisms have been proposed to explain this atypical location, including alternative transcription initiation and alternative splicing. However, none of these have been unequivocally established as occurring in live cells. Here we provide direct experimental evidence that in live intact cells, under certain stress conditions, clusterin can evade the secretion pathway and reach the cytosol. This was demonstrated using several complementary approaches. Flow cytometry and selective permeabilization of U251 cell membranes with digitonin allowed detection of cytosolic clusterin in stressed U251 cells. In addition, a stringent enzymatic assay reliant upon the exclusively cytosolic deubiquitinase enzymes confirmed that clusterin synthesized with its hydrophobic secretion signal sequence can reach the cytosol of U251 cells. The retrotranslocation of clusterin is likely to occur through a mechanism similar to the endoplasmic reticulum (ER)‐associated protein degradation pathway and involves passage through the Golgi apparatus. We also report that the ER‐associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The possible biological functions of these novel behaviours of clusterin are discussed.

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“…In cytoprotection a role may be played by clusterin, a molecule with a chaperon‐like activity, whose secretory form contributes to clearing cell debris from traumatized tissue (52,53). The presecretory form of clusterin ( ca 60 kDa) could be glycosylated and cloven into ca 40 kDa α‐ and β‐subunits which are held together by disulfide bonds (54).…”

Section: Discussionmentioning

confidence: 99%

NF‐κB is Not Directly Responsible for Photoresistance Induced by Fractionated Light Delivery in HT‐29 Colon Adenocarcinoma Cells

Kuliková

Mikeš

Hýžďalová

et al. 2010

Photochem & Photobiology

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Our recent study follows up an earlier one which demonstrated hypericin-mediated photocytotoxic effects on HT-29 adenocarcinoma cells by light fractionation with a longer dark pause between two unequal light doses (Sackova, A. [2005] Photochem. Photobiol.81, 1411-1416). Here, we present closer study on events invoked by sublethal light dose (1 J cm(-2)) during the period of 6 h that is sufficient to invoke resistance to second lethal dose (11 J cm(-2)). First, we proved that the dark pause of 6 h, but not 1 h, resulted in better cell survival with suppressed phosphatidylserine externalization, decreased reactive oxygen species production and hypericin content as well as altered expression of HSP70, GRP94, clusterin, nuclear factor (NF)-κB, IκB-α or Mcl-1. NF-κB activity assay confirmed activation of this early-response pathway. However, inhibition of IκB (IKK) kinase by parthenolide by stopping NF-κB release from the complex with IκB did not prevent onset of resistance, but it invoked some resistance even in groups with shorter, 1 h dark pause. Therefore, we predict involvement of another signaling pathway, located upstream from NF-κB, responsible for onset of resistance to photodynamic therapy with hypericin in colon adenocarcinoma cells HT-29.

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Clusterin proteins: stress-inducible polypeptides with proposed functions in multiple organ dysfunction

Cited by 13 publications

References 39 publications

Low dose IR-induced IGF-1-sCLU expression: a p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect

Low dose IR-induced IGF-1-sCLU expression: a p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect

Stress‐Induced Retrotranslocation of Clusterin/ApoJ into the Cytosol

NF‐κB is Not Directly Responsible for Photoresistance Induced by Fractionated Light Delivery in HT‐29 Colon Adenocarcinoma Cells

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