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Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol

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Abstract

Regulation of intracellular cholesterol homeostasis exists under balance between intracellular biosynthesis and uptake from extracellular origin by cell surface transport proteins. Expected role of cholesterol on either tumor suppressor gene and/or DNA synthesis has been aimed in the present study to explore intracellular cholesterol homeostasis in CLL subjects. Higher expressions of p53R2 (p53 dependent subunit of ribonucleotide reductase) and p53 were found in lymphocytes of chronic human lymphocytic leukemia as comparison to their normal counterparts. Inverse relation was found with p53 independent R2 subunit (in human hRRM2) of ribonucleotide reductase, which was found to be decreased from its control group. More expression of peripheral type benzodiazepine receptor, a cholesterol transporter, was noticed in isolated nuclear fraction with simultaneous increase of cholesterol concentration in cytoplasmic and nuclear compartments. A parallel increase of cholesterol in cell nucleus with increased p53R2 expression shows priority of the involvement of cholesterol in the process of cell replication.

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References

  1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–15.

    Article  CAS  PubMed  Google Scholar 

  2. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052–7.

    Article  CAS  PubMed  Google Scholar 

  3. Levin TT, Li Y, Riskind J, Rai K. Depression, anxiety and quality of life in a chronic lymphocytic leukemia cohort. Gen Hosp Psychiatry. 2007;29(3):251–6.

    Article  PubMed  Google Scholar 

  4. Brown MS, Goldstein JL. Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci USA. 1979;76:3330–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Oppenheimer MJ, Oram JF, Bierman EL. Downregulation of high density lipoprotein receptor activity of cultured fibroblasts by platelet-derived growth factor. Arteriosclerosis. 1987;7(4):325–32.

    Article  CAS  PubMed  Google Scholar 

  6. Chen Y, Hughes-fullford M. Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator SREBP2. USA Int J Cancer. 2000;91:41–5.

    Article  Google Scholar 

  7. Gal D, Simpson ER, Porter JC, Snyder JM. Defective internalization of low density lipoprotein in epidermoid cervical cancer cell. J Cell Biol. 1982;92:597–603.

    Article  CAS  PubMed  Google Scholar 

  8. Papadopoulos V. Peripheral-type benzodiazepine = diazepam binding inhibitor receptor: biological role in steroidogenic cell function. Endocr Rev. 1993;14:222–40.

    CAS  PubMed  Google Scholar 

  9. Snyder SH, McEnery MW, Verma A. Molecular mechanisms of peripheral benzodiazepine receptors. Neurochem Res. 1990;15:119–23.

    Article  CAS  PubMed  Google Scholar 

  10. McEnery MW, Snowman AM, Trifiletti RR, Snyder SH. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci. 1992;89:3170–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Garnier M, Dimchev AB, Boujrad N, Price JM, Musto NA. Papadopoulos V. In vitro reconstitution of a functional peripheral-type benzodiazepine receptor from mouse Leydig tumor cells. Mol Pharmacol. 1994;45:201–11.

    CAS  PubMed  Google Scholar 

  12. Li H, Yao Z, Degenhardt B, Teper G, Papadopoulos V. Cholesterol binding at the cholesterol recognition amino acid consensus (CRAC) of the peripheral type benzodiazepine receptor and inhibition of steroidogenesis by an HIV TAT-CRAC peptide. Proc Natl Acad Sci. 2001;98:1267–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lacapére JJ, Delavoie F, Li H, Péranzi G, Maccario J, Papadopoulos V, et al. Structural and functional study of reconstituted peripheral benzodiazepine receptor (PBR). Biochem Biophys Res Commun. 2001;284:536–641.

    Article  PubMed  Google Scholar 

  14. Wang JK, Morgan JI, Spector S. Benzodiazepines that bind at peripheral sites inhibit cell proliferation. Proc Natl Acad Sci. 1984;81(3):753–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ikezaki K, Black KL. Stimulation of cell growth and DNA synthesis by peripheral benzodiazepine. Cancer Lett. 1990;49(2):115–20.

    Article  CAS  PubMed  Google Scholar 

  16. Bruce JH, Ramirez AM, Lin L, Oracion A, Agarwal RP, Norenberg MD. Peripheral-type benzodiazepines inhibit proliferation of astrocytes in culture. Brain Res. 1991;564:167–70.

    Article  CAS  PubMed  Google Scholar 

  17. Neary JT, Jorgensen SL, Oracion AM, Bruce JH, Norenberg MD. Inhibition of growth factor-induced DNA synthesis in astrocytes by ligands of peripheral-type benzodiazepine receptors. Brain Res. 1995;675:27–30.

    Article  CAS  PubMed  Google Scholar 

  18. Mukhopadhyay S, Mukherji S, Das SK. Increased expression of peripheral benzodiazepine receptor (PBR) in dimethylbenz[a]anthracene-induced mammary tumors in rats. Glycoconjugate. 2006;23:199–207.

    Article  CAS  Google Scholar 

  19. Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V. Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Res. 1999;59(4):831–42.

    CAS  PubMed  Google Scholar 

  20. Albi E, Viola Magni MP. The role of intranuclear lipids. Biol Cell. 2004;96:657–67.

    Article  CAS  PubMed  Google Scholar 

  21. Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature. 2000;404:42–9.

    Article  CAS  PubMed  Google Scholar 

  22. Cerqueira N, Pereira S, Fernandes PA, Ramos MJ. Overview of ribonucleotide reductase inhibitors: an appealing target in anti-tumour therapy. Curr Med Chem. 2005;12:1283–94.

    Article  CAS  PubMed  Google Scholar 

  23. Reichard P. From RNA to DNA, Why so many ribonucleotide reductases? Science. 1993;260:1773–7.

    Article  CAS  PubMed  Google Scholar 

  24. Nakano K, Balint E, Ashcroft M, Vousden KH. A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene. 2000;19:4283–9.

    Article  CAS  PubMed  Google Scholar 

  25. Link PA, Baer MR, James SR. p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. Cancer Res. 2008;68:9358–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu X, Zhou B, Xue L. Metastasis-suppressing potential of ribonucleotide reductase small subunit p53R2 in human cancer cells. Clin Cancer Res. 2006;12:6337–44.

    Article  CAS  PubMed  Google Scholar 

  27. Bøyum A, Scand J. Isolation of lymphocytes, granulocytes and macrophages. Immunol. 1976;5(Suppl. 5):9–15.

    Google Scholar 

  28. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.

    Article  CAS  PubMed  Google Scholar 

  29. Zlatkis A, Zak B, Boyle AU. A new method for direct determination of serum cholesterol. J Lab Clin Med. 1953;41:486.

    CAS  PubMed  Google Scholar 

  30. Burton K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J. 1956;62(2):315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wilkinson JH. Enzyme kinetics and its relevance to enzyme assay. J Clin Path. 1971;24:14–21.

    Google Scholar 

  32. Albi E, Cataldi S, Rossi G, Viola Magni MP. A possible role of cholesterol-sphingomyelin/phosphatidylcholine in nuclear matrix during rat liver regeneration. J Hepatol. 2003;38:623–8.

    Article  CAS  PubMed  Google Scholar 

  33. Albi E, Pieroni S, Viola-Magni MP, Sartori C. Chromatin sphingomyelin changes in cell proliferation and/or apoptosis induced by ciprofibrate. J Cell Physiol. 2003;196:354–61.

    Article  CAS  PubMed  Google Scholar 

  34. Hardwick M, Cavalli LR, Barlow KD, Haddad BR, Papadopoulos V. Peripheral-type benzodiazepine receptor (PBR) gene amplification in MDA-MB-231 aggressive breast cancer cells. Cancer Genet Cytogenet. 2002;139(1):48–51.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by AIIMS internal grant. Grant number: F.6-1/2008-Acad. (PM).

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Correspondence to N. C. Chandra.

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Conflict of interest

Ankit Verma declares that he has no conflict of interest. N. C. Chandra declares that he has no conflict of interest.

Human and Animal Rights

The study was performed using human blood samples. The participants included were chronic lymphocytic leukemia patients and age-matched healthy controls.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics approval reference number: IESC/T-66/03.02.2012.

Additional information

The work was done completely in Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi-110029.

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Verma, A., Chandra, N.C. Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol. Ind J Clin Biochem 31, 336–341 (2016). https://doi.org/10.1007/s12291-015-0539-4

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  • DOI: https://doi.org/10.1007/s12291-015-0539-4

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