Repression of IR-Inducible Clusterin Expression by the p53 Tumor Suppressor Protein

Criswell, Tracy; Klokov, Dmitry; Beman, Meghan; Lavik, John-Paul; Boothman, David A.

doi:10.4161/cbt.2.4.430

Cited by 88 publications

(86 citation statements)

References 38 publications

(47 reference statements)

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“…20 In this context, it is interesting that p53, an activator of the apoptotic cascade, can suppress basal as well as IR-induced sCLU expression in both MCF-7 (breast cancer) and HCT116 (colon cancer) cells by repressing CLU promoter activity and transcription. 17 Recent clinical results by our group appear to support this theory in vivo (Willis and Boothman et al, unpublished data), in which loss of functional p53 appears to result in lost nCLU function. We are currently working on the mechanism through which sCLU expression is downregulated by p53 and nCLU functionally lost if p53 is mutated or cells lose expression of this tumour suppressor.…”

Section: Clu Apoptosis and Cell Cycle Regulationmentioning

confidence: 75%

“…16 Elucidation of the function of CLU in cells after stress is clearly complicated by the recognition of two different forms of the protein which apparently have two separate functions in the cell. A number of studies 1,5,13,16,17 have demonstrated that overexpression of the full-length CLU mRNA that would produce, depending on where the translation would start from and in this case, nCLU, acts as a prodeath signal, inhibiting cell growth and survival. However, other studies 2,6,8,10,[17][18][19] have shown that CLU expression may exert cytoprotective properties.…”

Section: Clu Apoptosis and Cell Cycle Regulationmentioning

confidence: 99%

“…One proposed mechanism for this death process is through the activation of the p53 tumour suppressor gene. 17 This would apparently explain how progression towards high-grade and metastatic carcinoma leads to a shift from nCLU to sCLU expression, and that the role of CLU for tumour growth may be related to a pattern shift in its isoform production. 3 It is well known that apoptotic pathways are regulated via an orchestrated interplay of multiple activators (e.g.…”

Section: Clu Apoptosis and Cell Cycle Regulationmentioning

confidence: 99%

“…In addition to the function of CLU in mediating apoptosis, 1,5,13,16,17 increasing evidence supports an important function for CLU in DNA repair. 23 Interestingly, CLU has been identified as the first stress-inducible protein that is associated with the DNA-dependent protein kinase (DNA-PK) double-strand break (DSB) repair complex.…”

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 Apoptosis and Cell Cycle Regulationmentioning

confidence: 75%

Section: Clu Apoptosis and Cell Cycle Regulationmentioning

confidence: 99%

Section: Clu Apoptosis and Cell Cycle Regulationmentioning

confidence: 99%

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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“…These different isoforms of CLU have been suggested to be antiapoptotic 6,13 or proapoptotic. 7,10,12,[14][15][16] These controversial reports on the role of CLU might be related to specific proteomic profiles that are produced by different apoptotic stimuli (i.e. the general protein pattern of CLU and the relative ratio between different CLU isoforms).…”

mentioning

confidence: 99%

Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

et al. 2004

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Clusterin (CLU) is a secreted heterodimeric glycoprotein thatcan be produced almost ubiquitously in mammalians tissues.1Its gene expression is subjected to complex regulation and canchange enormously according to different stimuli.2 Cloned andidentified as the most potently induced gene in the regressingrat ventral prostate following androgen-ablation,3 CLU wasalmost simultaneously characterized and isolated by differentresearch groups working in widely divergent areas.2 CLU iscoded by a single copy gene, located on chromosome 8.4 Thegene codes for an initial precursor peptide glycosylated andcleaved into two a and b chains of 40 kDa each, held togetherby a unique five disulfide bond motif in the extracellular matureform.1 This secreted form of CLU has been suggested to act asa molecular chaperone following stress-induced injury,5clearing extracellular debris.6 However, it has been reportedthe existence of an inactive, cytoplasmic form of CLUproduced by alternative splicing that is converted by ionizingirradiation to a truncated mature nuclear isoform,7 which bindsthe Ku70/Ku80 complex in cell-free systems8 inhibiting cellgrowth and survival7 probably by a caspase-3-independentmechanism.9 Other alternative CLU isoforms, produced eitherby exon skipping10 or by post-translational modificationsactivated by apoptosis,11,12 were recently described. Thesedifferent isoforms of CLU have been suggested to beantiapoptotic6,13 or proapoptotic.7,10,12,14–16These controversial reports on the role of CLU might berelated to specific proteomic profiles that are produced bydifferent apoptotic stimuli (i.e. the general protein pattern ofCLU and the relative ratio between different CLU isoforms).This might explain why CLU has been involved in a plethora ofpathophysiological processes, including cell–cell and cell–matrix adhesion, cell differentiation, transformation, aging17,18and cancer,19 but its biological role still remains to be clearlyestablished. Reports suggesting that CLU may be a potentialtumor suppressor gene include the finding that CLU suppressesNF-kB activity and the metastatic phenotype ofneuroblastoma cells.20 We have previously reported that CLUoverexpression inhibits cell cycle progression of simian virus40(SV40)-immortalized human prostate PNT2 and PNT1Aepithelial cells.21To further assess the role of CLU in apoptotic processes wehave studied its expression pattern during the regulation ofcalcium homeostasis. Ca2þ is an important regulator ofapoptosis and cell survival.22,23,24 Both pathological increaseof Ca2þ concentration in the cytosol compartment byinophores25 and depletion of intracellular Ca2þ stores maytrigger apoptosis by disrupting intracellular architecture andallowing effectors to gain access to their substrates.24,26,27Activation of apoptotic endonucleases28 eliciting DNA cleavageand chromatin condensation has beenwell documented.29,30,31A tight buffering of intracellular Ca2þ is required for normalgrowth. In fact, apoptosis can be induced by Ca2þ mobilizationfrom intracellular pools,23,24,27 chelati...

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Radiation Biology of Targeted Radiotherapy

Murray

Weinfeld

2010

Monoclonal Antibody and Peptide‐Targeted Radiotherapy of Cancer

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Repression of IR-Inducible Clusterin Expression by the p53 Tumor Suppressor Protein

Cited by 88 publications

References 38 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

Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

Radiation Biology of Targeted Radiotherapy

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