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Clusterin-mediated apoptosis is regulated by adenomatous polyposis coli and is p21 dependent but p53 independent.

Abstract
Clusterin is a widely expressed glycoprotein that has been paradoxically observed to have both pro- and antiapoptotic functions. Recent reports suggest this apparent dichotomy of function may be related to two different isoforms, one secreted and cytoplasmic, the other nuclear. To clarify the functional role of clusterin in regulating apoptosis, we examined its expression in human colon cancer tissues and in human colon cancer cell lines. We additionally explored its expression and activity using models of adenomatous polyposis coli (APC)- and chemotherapy-induced apoptosis. Clusterin RNA and protein levels were decreased in colon cancer tissues largely devoid of wild-type APC when compared with matched normal tissue controls, suggesting a means for invasive cancers to avoid apoptosis. Conversely, induction of apoptosis by expression of wild-type APC or by treatment with chemotherapy led to increased clusterin RNA and protein levels localizing to apoptotic nuclei. We found that transient transfection of clusterin to colon cancer cell lines directly enhanced basal and chemotherapy-induced apoptosis. Clusterin-induced apoptosis was inhibited by antisense clusterin and was found to be highly dependent on p21 but not p53 expression, yet a deficit in p21 can be subverted by clusterin transfection. Collectively, these data support the hypothesis that nuclear clusterin function is proapoptotic when induced by APC or chemotherapy in the context of p21 expression. Absent of p21, clusterin in not induced, and apoptosis is significantly inhibited. These data support a potential therapeutic role for clusterin in enhancing chemotherapy-induced apoptosis and in promoting apoptosis in cells deficient in p21.
AuthorsTingan Chen, Joel Turner, Susan McCarthy, Maurizio Scaltriti, Saverio Bettuzzi, Timothy J Yeatman
JournalCancer research (Cancer Res) Vol. 64 Issue 20 Pg. 7412-9 (Oct 15 2004) ISSN: 0008-5472 [Print] United States
PMID15492264 (Publication Type: Journal Article)
Chemical References
  • Adenomatous Polyposis Coli Protein
  • CDKN1A protein, human
  • CLU protein, human
  • Clusterin
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Glycoproteins
  • Molecular Chaperones
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Tumor Suppressor Protein p53
Topics
  • Adenomatous Polyposis Coli Protein (biosynthesis, genetics, physiology)
  • Apoptosis (drug effects, physiology)
  • Cell Nucleus (metabolism)
  • Clusterin
  • Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins (physiology)
  • Down-Regulation
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genes, APC
  • Glycoproteins (biosynthesis, genetics, physiology)
  • Humans
  • Molecular Chaperones (biosynthesis, genetics, physiology)
  • Oligonucleotides, Antisense (genetics, pharmacology)
  • RNA, Messenger (biosynthesis, genetics)
  • Transfection
  • Tumor Suppressor Protein p53 (physiology)
  • Up-Regulation

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