miRNA mediated up-regulation of cochaperone p23 acts as an anti-apoptotic factor in childhood acute lymphoblastic leukemia.

p23 is a heat shock protein 90 (Hsp90) cochaperone that plays a significant role in estrogen receptor (ER) alpha signal transduction and telomerase activity; it is up-regulated in several cancers. Recent studies have found that high level of p23 may promote tumor progression and poor prognosis in breast cancer patients. p23 was found to be overexpressed in our previous microarray assay of 100 childhood acute lymphoblastic leukemia (ALL) bone marrow (BM) samples. In the present study, we verified the upregulation of p23 in clinical ALL samples, and identified p23 to be an anti-apoptotic factor in the process of chemotherapy. We also found that p23 was regulated by hsa-miR-101 which was down-regulated in childhood ALL cases. Altogether these data demonstrate that the misregulation of hsa-miR-101 contributes partly to the overexpression of p23 in childhood ALL. As an anti-apoptotic factor, p23 is able to be a potential target for anti-leukemic therapy.

[1]  G. Morin,et al.  Functional requirement of p23 and Hsp90 in telomerase complexes. , 1999, Genes & development.

[2]  B. Freeman,et al.  The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation , 2007, Proceedings of the National Academy of Sciences.

[3]  P. Saremaslani,et al.  ALG-2: a Ca2+ -binding modulator protein involved in cell proliferation and in cell death. , 2002, Biochimica et biophysica acta.

[4]  Caifu Chen,et al.  MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia , 2011, Haematologica.

[5]  D. Toft,et al.  In Vitro Reconstitution of Functional Hepadnavirus Reverse Transcriptase with Cellular Chaperone Proteins , 2002, Journal of Virology.

[6]  P. F. Nielsen,et al.  Properties of the co‐chaperone protein p23 erroneously attributed to ALG‐2 (apoptosis‐linked gene 2) , 2003, FEBS letters.

[7]  S. Nasim,et al.  Overexpression of telomerase-associated chaperone proteins in prostatic intraepithelial neoplasia and carcinomas. , 2008, Oncology reports.

[8]  S. Jackson,et al.  Stimulation of the weak ATPase activity of human hsp90 by a client protein. , 2002, Journal of molecular biology.

[9]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[10]  Y. Iwakura,et al.  Knockout mice lacking cPGES/p23, a constitutively expressed PGE2 synthetic enzyme, are peri-natally lethal. , 2007, Biochemical and biophysical research communications.

[11]  R. Myers,et al.  Research resource: enhanced genome-wide occupancy of estrogen receptor α by the cochaperone p23 in breast cancer cells. , 2012, Molecular endocrinology.

[12]  Nan Qiao,et al.  Gene expression-based classification and regulatory networks of pediatric acute lymphoblastic leukemia. , 2009, Blood.

[13]  B. Freeman,et al.  p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity , 2008, Molecular and Cellular Biology.

[14]  W. Wurst,et al.  The Hsp90 Cochaperone p23 Is Essential for Perinatal Survival , 2006, Molecular and Cellular Biology.

[15]  M. Murakami,et al.  Regulation of cytosolic prostaglandin E synthase by phosphorylation. , 2004, The Biochemical journal.

[16]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature reviews genetics.

[17]  M. Garabedian,et al.  The Cochaperone p23 Differentially Regulates Estrogen Receptor Target Genes and Promotes Tumor Cell Adhesion and Invasion , 2006, Molecular and Cellular Biology.

[18]  T. Smithgall,et al.  A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor. , 1996, Cell stress & chaperones.

[19]  B. Koller,et al.  cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E2 Synthesis , 2007, Molecular and Cellular Biology.

[20]  J. W. Turner,et al.  Stable Association of hsp90 and p23, but Not hsp70, with Active Human Telomerase* , 2001, The Journal of Biological Chemistry.

[21]  J. Koivukangas,et al.  The terminal prostaglandin synthases mPGES‐1, mPGES‐2, and cPGES are all overexpressed in human gliomas , 2009, Neuropathology : official journal of the Japanese Society of Neuropathology.

[22]  J. Vandekerckhove,et al.  Caspase-dependent, geldanamycin-enhanced cleavage of co-chaperone p23 in leukemic apoptosis , 2004, Leukemia.

[23]  Han-Woong Lee,et al.  Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice , 2011, International journal of experimental pathology.

[24]  Makoto Murakami,et al.  Molecular Identification of Cytosolic Prostaglandin E2 Synthase That Is Functionally Coupled with Cyclooxygenase-1 in Immediate Prostaglandin E2Biosynthesis* , 2000, The Journal of Biological Chemistry.

[25]  L. Pearl,et al.  Crystal structure of an Hsp90–nucleotide–p23/Sba1 closed chaperone complex , 2006, Nature.

[26]  D. Toft,et al.  The Influence of ATP and p23 on the Conformation of hsp90* , 2002, The Journal of Biological Chemistry.

[27]  S. Logan,et al.  High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance. , 2010, Cancer research.

[28]  M. Murakami,et al.  Regulation of cytosolic prostaglandin E2 synthase by 90-kDa heat shock protein. , 2003, Biochemical and biophysical research communications.