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• W2000568937 abstract "Molecular defects in apoptotic pathways are thought to often contribute to the abnormal expansion of malignant cells and their resistance to chemotherapy. Therefore, a comprehensive knowledge of the mechanisms controlling induction of apoptosis and subsequent cellular disintegration could result in improved methods for prognosis and treatment of cancer. In this study, we have examined apoptosis-induced alterations in two proteins, nucleolin and poly(ADP-ribose) polymerase-1 (PARP-1), in U937 leukemia cells. Nucleolin is expressed at high levels in malignant cells, and it is a multifunctional and mobile protein that can shuttle among the nucleolus, nucleoplasm, cytoplasm, and plasma membrane. Here, we report our findings that UV irradiation or camptothecin treatment of U937 cells induced apoptosis and caused a significant change in the levels and localization of nucleolin within the nucleus. Additionally, nucleolin levels were dramatically decreased in extracts containing the cytoplasm and plasma membrane. These alterations could be abrogated by pre-incubation with an inhibitor of PARP-1 (3-aminobenzamide), and our data support a potential role for nucleolin in removing cleaved PARP-1 from dying cells. Furthermore, both nucleolin and cleaved PARP-1 were detected in the culture medium of cells undergoing apoptosis, associated with particles of a size consistent with apoptotic bodies. These results indicate that nucleolin plays an important role in apoptosis, and could be a useful marker for assessing apoptosis or detecting apoptotic bodies. In addition, the data provide a possible explanation for the appearance of nucleolin and PARP-1 autoantibodies in some autoimmune diseases. Molecular defects in apoptotic pathways are thought to often contribute to the abnormal expansion of malignant cells and their resistance to chemotherapy. Therefore, a comprehensive knowledge of the mechanisms controlling induction of apoptosis and subsequent cellular disintegration could result in improved methods for prognosis and treatment of cancer. In this study, we have examined apoptosis-induced alterations in two proteins, nucleolin and poly(ADP-ribose) polymerase-1 (PARP-1), in U937 leukemia cells. Nucleolin is expressed at high levels in malignant cells, and it is a multifunctional and mobile protein that can shuttle among the nucleolus, nucleoplasm, cytoplasm, and plasma membrane. Here, we report our findings that UV irradiation or camptothecin treatment of U937 cells induced apoptosis and caused a significant change in the levels and localization of nucleolin within the nucleus. Additionally, nucleolin levels were dramatically decreased in extracts containing the cytoplasm and plasma membrane. These alterations could be abrogated by pre-incubation with an inhibitor of PARP-1 (3-aminobenzamide), and our data support a potential role for nucleolin in removing cleaved PARP-1 from dying cells. Furthermore, both nucleolin and cleaved PARP-1 were detected in the culture medium of cells undergoing apoptosis, associated with particles of a size consistent with apoptotic bodies. These results indicate that nucleolin plays an important role in apoptosis, and could be a useful marker for assessing apoptosis or detecting apoptotic bodies. In addition, the data provide a possible explanation for the appearance of nucleolin and PARP-1 autoantibodies in some autoimmune diseases. poly(ADP-ribose) polymerase-1 3-aminobenzamide phosphate-buffered saline 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide terminal dUTP nick-end labeling phosphate-buffered saline plus Tween 20 systemic lupus erythematosus Following treatment with chemotherapy agents or exposure to cellular stress such as heat shock or ionizing radiation, malignant cells can respond by undergoing apoptosis or necrosis, or may be resistant to treatment. The failure of malignant cells to undergo cell death in response to chemotherapy is a major cause of treatment failure (1Schimmer A.D. Hedley D.W. Penn L.Z. Minden M.D. Blood. 2001; 98: 3541-3553Google Scholar), and, in many cases, chemoresistance is associated with aberrant expression of the proteins involved in the activation and regulation of apoptosis (1Schimmer A.D. Hedley D.W. Penn L.Z. Minden M.D. Blood. 2001; 98: 3541-3553Google Scholar, 2Saikumar P. Dong Z. Mikhailov V. Denton M. Weinberg J.M. Venkatachalam M.A. Am. J. Med. 1999; 107: 489-506Google Scholar, 3Gascoyne R.D. Adomat S.A. Krajewski S. Krajewska M. Horsman D.E. Tolcher A.W. O'Reilly S.E. Hoskins P. Coldman A.J. Reed J.C. Connors J.M. Blood. 1997; 90: 244-251Google Scholar). Consequently, several therapeutic strategies based on modulating apoptotic pathways are currently in development (4Johnstone R.W. Ruefli A.A. Lowe S.W. Cell. 2002; 108: 153-164Google Scholar, 5Makin G. Expert Opin. Ther. Targets. 2002; 6: 73-84Google Scholar).Apoptosis is characterized by well defined morphological and biochemical changes, which are generally mediated by a family of cysteine proteases, called caspases. There are at least two well characterized molecular mechanisms leading to caspase-dependent apoptosis, namely receptor-mediated and mitochondrial pathways, which have been described in some detail in recent reviews (1Schimmer A.D. Hedley D.W. Penn L.Z. Minden M.D. Blood. 2001; 98: 3541-3553Google Scholar, 2Saikumar P. Dong Z. Mikhailov V. Denton M. Weinberg J.M. Venkatachalam M.A. Am. J. Med. 1999; 107: 489-506Google Scholar). Both pathways lead to activation of caspase-3, which ultimately results in fragmentation of chromosomal DNA and proteolysis of selected nuclear proteins. The aim of the present study is to investigate the role of nucleolin during apoptosis of leukemia cells treated with the chemotherapy agent, camptothecin, or irradiated with UV light, and to examine the relationship between changes in nucleolin and effects on poly(ADP-ribose) polymerase-1 (PARP-1).1Human nucleolin is a 707-amino acid protein consisting of an acidic histone-like N terminus, a central domain containing four RNA binding domains, and a C terminus that is rich in arginine and glycine (RGG repeats). This multidomain structure reflects the diverse roles of nucleolin in cell growth, proliferation, and death, which have been recently highlighted in several excellent reviews (6Srivastava M. Pollard H.B. FASEB J. 1999; 13: 1911-1922Google Scholar, 7Ginisty H. Sicard H. Roger B. Bouvet P. J. Cell Sci. 1999; 112: 761-772Google Scholar, 8Tuteja R. Tuteja N. Crit. Rev. Biochem. Mol. Biol. 1998; 33: 407-436Google Scholar). Nucleolin has been implicated in many cellular processes, including transcription, packing, and transport of ribosomal RNA, replication and recombination of DNA, cell cycle progression, and apoptosis (6Srivastava M. Pollard H.B. FASEB J. 1999; 13: 1911-1922Google Scholar, 7Ginisty H. Sicard H. Roger B. Bouvet P. J. Cell Sci. 1999; 112: 761-772Google Scholar, 8Tuteja R. Tuteja N. Crit. Rev. Biochem. Mol. Biol. 1998; 33: 407-436Google Scholar, 9Daniely Y. Borowiec J.A. J. Cell Biol. 2000; 149: 799-810Google Scholar, 10Wang Y. Guan J. Wang H. Wang Y. Leeper D. Iliakis G. J. Biol. Chem. 2001; 276: 20579-20588Google Scholar, 11Borggrefe T. Wabl M. Akhmedov A.T. Jessberger R. J. Biol. Chem. 1998; 273: 17025-17035Google Scholar, 12Dempsey L.A. Sun H. Hanakahi L.A. Maizels N. J. Biol. Chem. 1999; 274: 1066-1071Google Scholar, 13Sirri V. Roussel P. Hernandez-Verdun D. Micron. 2000; 31: 121-126Google Scholar, 14Brockstedt E. Rickers A. Kostka S. Laubersheimer A. Dorken B. Wittmann-Liebold B. Bommert K. Otto A. J. Biol. Chem. 1998; 273: 28057-28064Google Scholar). Although generally considered a predominantly nucleolar protein, nucleolin appears to be very mobile and can also be present in the nucleoplasm and cytoplasm and on the cell surface (9Daniely Y. Borowiec J.A. J. Cell Biol. 2000; 149: 799-810Google Scholar, 10Wang Y. Guan J. Wang H. Wang Y. Leeper D. Iliakis G. J. Biol. Chem. 2001; 276: 20579-20588Google Scholar, 15Borer R.A. Lehner C.F. Eppenberger H.M. Nigg E.A. Cell. 1989; 56: 79-90Google Scholar, 16Larrucea S. Cambronero R. Gonzalez-Rubio C. Fraile B. Gamallo C. Fontan G. Lopez-Trascasa M. Biochem. Biophys. Res. Commun. 1999; 266: 51-57Google Scholar, 17Callebaut C. Blanco J. Benkirane N. Krust B. Jacotot E. Guichard G. Seddiki N. Svab J. Dam E. Muller S. Briand J.P. Hovanessian A.G. J. Biol. Chem. 1998; 273: 21988-21997Google Scholar, 18Hovanessian A.G. Puvion-Dutilleul F. Nisole S. Svab J. Perret E. Deng J.S. Krust B. Exp. Cell Res. 2000; 261: 312-328Google Scholar, 19Dumler I. Stepanova V. Jerke U. Mayboroda O.A. Vogel F. Bouvet P. Tkachuk V. Haller H. Gulba D.C. Curr. Biol. 1999; 9: 1468-1476Google Scholar). In fact, there are several reports describing redistribution of nucleolin within the cell in response to a number of stimuli, including heat shock (9Daniely Y. Borowiec J.A. J. Cell Biol. 2000; 149: 799-810Google Scholar, 10Wang Y. Guan J. Wang H. Wang Y. Leeper D. Iliakis G. J. Biol. Chem. 2001; 276: 20579-20588Google Scholar), mitosis (20Weisenberger D. Scheer U. J. Cell Biol. 1995; 129: 561-575Google Scholar), T cell activation (21Gil D. Gutierrez D. Alarcon B. J. Biol. Chem. 2001; 276: 11174-11179Google Scholar), treatment with a cyclin-dependent kinase inhibitor (22David-Pfeuty T. Oncogene. 1999; 18: 7409-7422Google Scholar), and viral infection (23Matthews D.A. J. Virol. 2001; 75: 1031-1038Google Scholar, 24Waggoner S. Sarnow P. J. Virol. 1998; 72: 6699-6709Google Scholar, 25Cannavo' G. Paiardini M. Galati D. Cervasi B. Montroni M. De Vico G. Guetard D. Bocchino M.L. Picerno I. Magnani M. Silvestri G. Piedimonte G. Blood. 2001; 97: 1756-1764Google Scholar).There is considerable interest in studying nucleolin function, not only because it is involved in so many fundamental processes, but also because of the significance of nucleolin expression in malignant cells. Levels of nucleolin are positively correlated with cellular proliferation (26Derenzini M. Sirri V. Trere D. Ochs R.L. Lab. Invest. 1995; 73: 497-502Google Scholar) and high levels of silver-staining nucleolar proteins (of which nucleolin is the major component) predict a poor prognosis in many types of cancer (27Derenzini M. Micron. 2000; 31: 117-120Google Scholar). We have proposed nucleolin as a novel target for therapeutic intervention, based on our finding that G-rich oligonucleotides that bind to nucleolin protein can inhibit proliferation and induce apoptosis in many cell lines derived from solid tumors (28Bates P.J. Kahlon J.B. Thomas S.D. Trent J.O. Miller D.M. J. Biol. Chem. 1999; 274: 26369-26377Google Scholar, 29Xu X. Hamhouyia F. Thomas S.D. Burke T.J. Girvan A.C. McGregor W.G. Trent J.O. Miller D.M. Bates P.J. J. Biol. Chem. 2001; 276: 43221-43230Google Scholar, 30Dapic V. Bates P.J. Trent J.O. Rodger A. Thomas S.D. Miller D.M. Biochemistry. 2002; 41: 3676-3685Google Scholar) and leukemias (31Castillos F.A. Bates P.J. Thomas S.D. Xu X.H. Trent J.O. Miller D.M. Blood. 2000; 96: 1331Google Scholar).The levels and characteristics of PARP-1 protein have also been examined in this study for two reasons. First, PARP-1 cleavage is a characteristic feature of apoptosis and the timing of apoptosis-associated events is often determined relative to the onset of PARP-1 cleavage. Second, it has been reported that nucleolin can form a complex with PARP-1 in B-cells (11Borggrefe T. Wabl M. Akhmedov A.T. Jessberger R. J. Biol. Chem. 1998; 273: 17025-17035Google Scholar) and in kidney cells (32Yanagida M. Shimamoto A. Nishikawa K. Furuichi Y. Isobe T. Takahashi N. Proteomics. 2001; 1: 1390-1404Google Scholar), suggesting that PARP-1 could potentially be involved in the regulation of nucleolin function, or vice versa.PARP-1 catalyzes the addition of poly(ADP-ribose) chains to a number of nuclear proteins in response to DNA damage. It is clear that this short-lived post-translational modification plays an important, although incompletely defined, role in DNA damage response and apoptosis (33D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Google Scholar, 34Smulson M.E. Simbulan-Rosenthal C.M. Boulares A.H. Yakovlev A. Stoica B. Iyer S. Luo R. Haddad B. Wang Z.Q. Pang T. Jung M. Dritschilo A. Rosenthal D.S. Adv. Enzyme Regul. 2000; 40: 183-215Google Scholar). PARP-1 enzymatic activity is dependent upon binding to DNA strand breaks and is rapidly activated in response to cellular stresses, such as heat shock, gamma radiation, exposure to carcinogens, and treatment with chemotherapy agents. Synthesis of poly(ADP-ribose) uses nicotinamide adenosine dinucleotide (NAD+), and cleavage of PARP-1 during apoptosis is thought to occur to conserve NAD+ and allow production of ATP, which is needed for execution of apoptosis. This cleavage appears to be a universal part of the apoptotic process, and appearance of the 89- and 24-kDa proteolytic fragments of PARP-1 has become one of the classical hallmarks of apoptosis (33D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Google Scholar, 34Smulson M.E. Simbulan-Rosenthal C.M. Boulares A.H. Yakovlev A. Stoica B. Iyer S. Luo R. Haddad B. Wang Z.Q. Pang T. Jung M. Dritschilo A. Rosenthal D.S. Adv. Enzyme Regul. 2000; 40: 183-215Google Scholar).Here, we describe the effect of apoptosis in U937 leukemia cells on the expression of nucleolin and PARP-1 proteins. Because nucleolin can translocate between different cellular compartments, alterations in nucleolin in both nuclear (containing the nucleoli and nucleoplasm) and S-100 (containing the cytoplasm and plasma membrane) extracts have been evaluated.DISCUSSIONThere are a number of reasons why studying nucleolin function and regulation is of interest. First, nucleolin is a fascinating protein because of its multifunctionality and its ability to translocate within the cell, yet the reasons for its ubiquitous behavior have not been fully elucidated (6Srivastava M. Pollard H.B. FASEB J. 1999; 13: 1911-1922Google Scholar, 7Ginisty H. Sicard H. Roger B. Bouvet P. J. Cell Sci. 1999; 112: 761-772Google Scholar, 8Tuteja R. Tuteja N. Crit. Rev. Biochem. Mol. Biol. 1998; 33: 407-436Google Scholar). Second, nucleolin is associated with many of the processes that are dysfunctional in neoplastic cells (proliferation, cell cycle control, apoptosis) and elevated levels of nucleolin expression are generally related to malignancy (26Derenzini M. Sirri V. Trere D. Ochs R.L. Lab. Invest. 1995; 73: 497-502Google Scholar, 27Derenzini M. Micron. 2000; 31: 117-120Google Scholar). Third, we have identified nucleolin as the probable molecular target of a class of non-antisense G-rich oligonucleotides that inhibit the proliferation of tumor and leukemia cell lines, and therefore have significant promise as novel therapeutic agents (28Bates P.J. Kahlon J.B. Thomas S.D. Trent J.O. Miller D.M. J. Biol. Chem. 1999; 274: 26369-26377Google Scholar, 29Xu X. Hamhouyia F. Thomas S.D. Burke T.J. Girvan A.C. McGregor W.G. Trent J.O. Miller D.M. Bates P.J. J. Biol. Chem. 2001; 276: 43221-43230Google Scholar, 30Dapic V. Bates P.J. Trent J.O. Rodger A. Thomas S.D. Miller D.M. Biochemistry. 2002; 41: 3676-3685Google Scholar, 31Castillos F.A. Bates P.J. Thomas S.D. Xu X.H. Trent J.O. Miller D.M. Blood. 2000; 96: 1331Google Scholar).In this report, we have described alterations in the levels and localization of nucleolin protein that occur in leukemia cells induced to undergo apoptosis by UV-irradiation or treatment with the topoisomerase I inhibitor, camptothecin. We found that induction of apoptosis was accompanied by a rapid reduction in the levels of nuclear nucleolin, followed several hours later by the disappearance of nucleolin from the S-100 fraction containing plasma membrane nucleolin. A distinct redistribution of nucleolin within the nucleus and the appearance of extracellular apoptotic bodies containing nucleolin and PARP-1 were also observed. By examining levels and localization of nucleolin in relation to other apoptosis-induced changes, we have shown that alterations in nucleolin occur very early in the apoptotic process. For example, at 1 h following UV irradiation of cells (for 30 s), nucleosomal fragmentation of DNA is barely detectable on ethidium-stained agarose gels, and only ∼50% of PARP-1 has been cleaved. At the same time point, levels of nuclear nucleolin are clearly reduced, a distinct alteration in the staining pattern of nuclear nucleolin can be observed, and low levels of nucleolin-containing apoptotic bodies can be detected (Figs. 4 and 6, and data not shown). The fact that alterations in nucleolin are such an early event may indicate that this protein plays an active role in the initiation or progression of apoptosis, although further experiments would be required to confirm this.Previously, there have been several studies that have examined the role of nucleolin in cell death. Martelli et al. (47Martelli A.M. Robuffo I. Bortul R. Ochs R.L. Luchetti F. Cocco L. Zweyer M. Bareggi R. Falcieri E. J. Cell. Biochem. 2000; 78: 264-277Google Scholar, 48Bortul R. Zweyer M. Billi A.M. Tabellini G. Ochs R.L. Bareggi R. Cocco L. Martelli A.M. J. Cell. Biochem. 2001; 81: 19-31Google Scholar, 49Martelli A.M. Zweyer M. Ochs R.L. Tazzari P.L. Tabellini G. Narducci P. Bortul R. J. Cell. Biochem. 2001; 82: 634-646Google Scholar) have used light and electron microscopy to examine changes in nucleolar proteins in HL60 leukemia cells treated with camptothecin (to induce apoptosis) or ethanol (to induce necrosis). These authors reported a redistribution (associated with fragmentation of nuclei) of nucleolin in apoptotic cells but not necrotic cells, and found that nucleolin was not degraded during apoptosis, in agreement with our data. In contrast to our results and those of Martelli and colleagues, several other reports suggest that nucleolin is proteolyzed in response to apoptosis. Brockstedt et al. (14Brockstedt E. Rickers A. Kostka S. Laubersheimer A. Dorken B. Wittmann-Liebold B. Bommert K. Otto A. J. Biol. Chem. 1998; 273: 28057-28064Google Scholar) used two-dimensional electrophoresis to identify nucleolin as a protein that was cleaved in response to anti-IgM antibody-mediated apoptosis in a Burkitt's lymphoma cell line. Morimoto et al. (50Morimoto Y. Kito S. Ohba T. Morimoto H. Okamura H. Haneji T. J. Oral Pathol. Med. 2001; 30: 193-199Google Scholar) described the proteolysis of a 110-kDa silver-stained nucleolar protein (presumed to be nucleolin) to give a 80-kDa fragment when human salivary gland or oral carcinoma cells were treated with okadaic acid. Finally, Pasternack et al. (51Pasternack M.S. Bleier K.J. McInerney T.N. J. Biol. Chem. 1991; 266: 14703-14708Google Scholar) reported that nucleolin was a substrate (in vitro) for cleavage by granzyme A, an apoptosis-associated protease secreted by cytotoxic T lymphocytes. The seemingly contradictory findings regarding apoptosis-induced cleavage of nucleolin could potentially be caused by cell death occurring via different mechanisms. Although the precise apoptotic pathways for each treatment are far from clear, it seems reasonable to expect that DNA damage (such as UV irradiation or camptothecin treatment) could activate a different pathway from anti-IgM, which binds to B-cell surface receptors (14Brockstedt E. Rickers A. Kostka S. Laubersheimer A. Dorken B. Wittmann-Liebold B. Bommert K. Otto A. J. Biol. Chem. 1998; 273: 28057-28064Google Scholar), or okadaic acid, which is known to up-regulate Fas receptor (52Morimoto Y. Morimoto H. Okamura H. Nomiyama K. Nakamuta N. Kobayashi S. Kito S. Ohba T. Haneji T. Arch. Oral Biol. 2000; 45: 657-666Google Scholar).The apoptosis-induced changes in nucleolin levels that we have described appear to depend in some way upon PARP-1, inasmuch as an inhibitor of PARP-1 (3-ABA) can repress them. Further studies will be required to determine whether this is related to poly(ADP-ribosyl)ation of nucleolin by PARP-1, or the binding of nucleolin to the 89-kDa fragment of PARP-1 (or perhaps both). In accord with our observations, previous reports have also described redistribution of 89-kDa PARP-1 in response to apoptosis (53Soldani C. Lazze M.C. Bottone M.G. Tognon G. Biggiogera M. Pellicciari C.E. Scovassi A.I. Exp. Cell Res. 2001; 269: 193-201Google Scholar, 54Soldani C. Bottone M.G. Pellicciari C. Scovassi A.I. Eur. J. Histochem. 2001; 45: 389-392Google Scholar, 55Alvarez-Gonzalez R. Spring H. Muller M. Burkle A. J. Biol. Chem. 1999; 274: 32122-32126Google Scholar). Indeed, PARP-1 can be localized in the nucleolus under some circumstances (53Soldani C. Lazze M.C. Bottone M.G. Tognon G. Biggiogera M. Pellicciari C.E. Scovassi A.I. Exp. Cell Res. 2001; 269: 193-201Google Scholar, 54Soldani C. Bottone M.G. Pellicciari C. Scovassi A.I. Eur. J. Histochem. 2001; 45: 389-392Google Scholar, 55Alvarez-Gonzalez R. Spring H. Muller M. Burkle A. J. Biol. Chem. 1999; 274: 32122-32126Google Scholar, 56Desnoyers S. Kaufmann S.H. Poirier G.G. Exp. Cell Res. 1996; 227: 146-153Google Scholar), and there is some evidence to suggest that the nucleolus is central to the process of apoptosis and the earliest site of caspase-mediated proteolysis (57Horky M. Wurzer G. Kotala V. Anton M. Vojtesek B. Vacha J. Wesierska-Gadek J. J. Cell Sci. 2001; 114: 663-670Google Scholar, 58Stegh A.H. Schickling O. Ehret A. Scaffidi C. Peterhansel C. Hofmann T.G. Grummt I. Krammer P.H. Peter M.E. EMBO J. 1998; 17: 5974-5986Google Scholar).Another novel result of our study is the observation that nucleolin appears to be shed from apoptotic cells in the form of small bodies. Kerr et al. (43Kerr J.F. Wyllie A.H. Currie A.R. Br. J. Cancer. 1972; 26: 239-257Google Scholar) first described apoptotic bodies in 1972, and since then several others types of apoptosis-associated particles, including nucleolar-derived structures, have been reported (59Biggiogera M. Pellicciari C. FASEB J. 2000; 14: 28-34Google Scholar, 60Halicka H.D. Bedner E. Darzynkiewicz Z. Exp. Cell Res. 2000; 260: 248-256Google Scholar). Apoptotic bodies are thought to be derived from collapsing nuclei, which are transported to the plasma membrane and released into the extracellular space, where they are normally cleared by phagocytosis (61Eguchi K. Intern. Med. 2001; 40: 275-284Google Scholar). Although apoptotic bodies have not been extensively characterized, they are known to contain several components including DNA or RNA, plasma membrane components, and nuclear matrix proteins (49Martelli A.M. Zweyer M. Ochs R.L. Tazzari P.L. Tabellini G. Narducci P. Bortul R. J. Cell. Biochem. 2001; 82: 634-646Google Scholar, 60Halicka H.D. Bedner E. Darzynkiewicz Z. Exp. Cell Res. 2000; 260: 248-256Google Scholar).The presence of nucleolin in apoptotic bodies has a number of clinical implications. In healthy individuals, apoptotic bodies are engulfed by macrophages or neighboring cells, and cleared from the circulation. However, under conditions of excessive apoptosis, apoptotic bodies may be released into the circulation (61Eguchi K. Intern. Med. 2001; 40: 275-284Google Scholar) and could potentially be detected in plasma or serum. This excessive apoptosis can be caused by a number of conditions including inflammation, autoimmune disease, ischemic injury, and cancer. There is evidence that the presence of apoptotic cells or bodies can be an important diagnostic or prognostic marker for several types of cancer (45Sohn J.H. Kim D.H. Choi N.G. Park Y.E. Ro J.Y. Histopathology. 2000; 37: 555-560Google Scholar, 62de Jong J.S. van Diest P.J. Baak J.P. Br. J. Cancer. 2000; 82: 368-373Google Scholar, 63Brustmann H. Pathol. Res. Pract. 2002; 198: 85-90Google Scholar, 64Ghosh M. Crocker J. Morris A. J. Clin. Pathol. 2001; 54: 111-115Google Scholar) and detection of circulating apoptotic material (e.g. nucleosomes or nucleic acids) in serum has been proposed as a non-invasive method to detect the presence of malignancy or to evaluate therapeutic response in cancer patients receiving chemotherapy or radiation (65Holdenrieder S. Stieber P. Bodenmuller H. Busch M. Von Pawel J. Schalhorn A. Nagel D. Seidel D. Ann. N. Y. Acad. Sci. 2001; 945: 93-102Google Scholar, 66Lichtenstein A.V. Melkonyan H.S. Tomei L.D. Umansky S.R. Ann. N. Y. Acad. Sci. 2001; 945: 239-249Google Scholar). Nucleolin may be a particularly useful marker for apoptosis in these applications because tumor-derived apoptotic bodies are expected to be rich in nucleolin. The ability of apoptotic bodies to deliver their contents to the cells that engulf them is also an interesting property, which has been linked to the horizontal transfer of oncogenes (67Bergsmedh A. Szeles A. Henriksson M. Bratt A. Folkman M.J. Spetz A.L. Holmgren L. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6407-6411Google Scholar, 68Holmgren L. Szeles A. Rajnavolgyi E. Folkman J. Klein G. Ernberg I. Falk K.I. Blood. 1999; 93: 3956-3963Google Scholar) and exploited as a drug delivery mechanism (69Ma J. Reed K.A. Gallo J.M. Cancer Res. 2002; 62: 1382-1387Google Scholar).Our data also have implications for some autoimmune diseases, which are thought to develop, at least in part, because of defects in apoptotic responses (2Saikumar P. Dong Z. Mikhailov V. Denton M. Weinberg J.M. Venkatachalam M.A. Am. J. Med. 1999; 107: 489-506Google Scholar, 61Eguchi K. Intern. Med. 2001; 40: 275-284Google Scholar). Autoimmune diseases are characterized by the development of autoreactive T-cells and B-cells against self-antigens, and there is mounting evidence that this response could be triggered by exposure of the immune system to excessive amounts of intracellular materials from apoptotic cells (70Casciola-Rosen L.A. Anhalt G. Rosen A. J. Exp. Med. 1994; 179: 1317-1330Google Scholar, 71Andrade F. Casciola-Rosen L. Rosen A. Rheum. Dis. Clin. N. Am. 2000; 26: 215Google Scholar, 72Gensler T.J. Hottelet M. Zhang C. Schlossman S. Anderson P. Utz P.J. J. Autoimmun. 2001; 16: 59-69Google Scholar, 73Cocca B.A. Cline A.M. Radic M.Z. J. Immunol. 2002; 169: 159-166Google Scholar). The appearance of nucleolin autoantibodies is one of the hallmarks of the autoimmune disease systemic lupus erythematosus (SLE), and these are in fact some of the earliest autoantibodies to develop as the disease progresses (74Minota S. Jarjour W.N. Suzuki N. Nojima Y. Roubey R.A. Mimura T. Yamada A. Hosoya T. Takaku F. Winfield J.B. J. Immunol. 1991; 146: 2249-2252Google Scholar, 75Hirata D. Iwamoto M. Yoshio T. Okazaki H. Masuyama J. Mimori A. Minota S. Clin. Immunol. 2000; 97: 50-58Google Scholar). Our observation that apoptotic bodies containing nucleolin are rapidly shed from cells undergoing apoptosis suggests a possible explanation for the early appearance of nucleolin autoantibodies in SLE. Patients with SLE also have a high frequency of PARP-1 autoantibodies (76Lim Y. Lee D.Y. Lee S. Park S.Y. Kim J. Cho B. Lee H. Kim H.Y. Lee E. Song Y.W. Jeoung D.I. Biochem. Biophys. Res. Commun. 2002; 295: 119-124Google Scholar).In conclusion, our studies have identified nucleolin as an important component of the apoptotic pathway in leukemia cells. Although we have not yet elucidated its precise role in this complex process, our results indicate that nucleolin may be involved in the processing of a proteolytic fragment of PARP-1. Furthermore, the distinct nuclear redistribution of nucleolin, its disappearance from the plasma membrane, and its presence in apoptotic bodies may be useful markers to detect apoptosis in experimental and whole animal systems. Following treatment with chemotherapy agents or exposure to cellular stress such as heat shock or ionizing radiation, malignant cells can respond by undergoing apoptosis or necrosis, or may be resistant to treatment. The failure of malignant cells to undergo cell death in response to chemotherapy is a major cause of treatment failure (1Schimmer A.D. Hedley D.W. Penn L.Z. Minden M.D. Blood. 2001; 98: 3541-3553Google Scholar), and, in many cases, chemoresistance is associated with aberrant expression of the proteins involved in the activation and regulation of apoptosis (1Schimmer A.D. Hedley D.W. Penn L.Z. Minden M.D. Blood. 2001; 98: 3541-3553Google Scholar, 2Saikumar P. Dong Z. Mikhailov V. Denton M. Weinberg J.M. Venkatachalam M.A. Am. J. Med. 1999; 107: 489-506Google Scholar, 3Gascoyne R.D. Adomat S.A. Krajewski S. Krajewska M. Horsman D.E. Tolcher A.W. O'Reilly S.E. Hoskins P. Coldman A.J. Reed J.C. Connors J.M. Blood. 1997; 90: 244-251Google Scholar). Consequently, several therapeutic strategies based on modulating apoptotic pathways are currently in development (4Johnstone R.W. Ruefli A.A. Lowe S.W. Cell. 2002; 108: 153-164Google Scholar, 5Makin G. Expert Opin. Ther. Targets. 2002; 6: 73-84Google Scholar). Apoptosis is characterized by well defined morphological and biochemical changes, which are generally mediated by a family of cysteine proteases, called caspases. There are at least two well characterized molecular mechanisms leading to caspase-dependent apoptosis, namely receptor-mediated and mitochondrial pathways, which have been described in some detail in recent reviews (1Schimmer A.D. Hedley D.W. Penn L.Z. Minden M.D. Blood. 2001; 98: 3541-3553Google Scholar, 2Saikumar P. Dong Z. Mikhailov V. Denton M. Weinberg J.M. Venkatachalam M.A. Am. J. Med. 1999; 107: 489-506Google Scholar). Both pathways lead to activation of caspase-3, which ultimately results in fragmentation of chromosomal DNA and proteolysis of selected nuclear proteins. The aim of the present study is to investigate the role of nucleolin during apoptosis of leukemia cells treated with the chemotherapy agent, camptothecin, or irradiated with UV light, and to examine the relationship between changes in nucleolin and effects on poly(ADP-ribose) polymerase-1 (PARP-1).1 Human nucleolin is a 707-amino acid protein consisting of an acidic histone-like N terminus, a central domain containing four RNA binding domains, and a C terminu" @default.
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• W2000568937 date "2003-03-01" @default.
• W2000568937 modified "2023-10-16" @default.
• W2000568937 title "Apoptosis in Leukemia Cells Is Accompanied by Alterations in the Levels and Localization of Nucleolin" @default.
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• W2000568937 doi "https://doi.org/10.1074/jbc.m207637200" @default.
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