Terminal differentiation and senescence share several common properties, including irreversible cessation of growth and changes in gene expression profiles. To identify molecules that converge in both processes, an overlapping pathway screening was employed that identified old-35, which is human polynucleotide phosphorylase (hPNPaseold-35), a 3′,5′-exoribonuclease. We previously demonstrated that hPNPaseold-35 is a type I interferon-inducible gene that is also induced in senescent fibroblasts. In vitro RNA degradation assays confirmed its exoribonuclease properties, and overexpression of hPNPaseold-35 resulted in growth suppression in HO-1 human melanoma cells. The present study examined the molecular mechanism of the growth-arresting property of hPNPaseold-35. When overexpressed by means of a replication-incompetent adenoviral vector (Ad.hPNPaseold-35), hPNPaseold-35 inhibited cell growth in all cell lines tested. Analysis of cell cycle revealed that infection of HO-1 cells with Ad.hPNPaseold-35 resulted in arrest in the G1 phase and eventually apoptosis accompanied by marked reduction in the S phase. Infection with Ad.hPNPaseold-35 resulted in reduction in expression of the c-myc mRNA and Myc protein and modulated the expression of proteins regulating G1 checkpoint and apoptosis. In vitro mRNA degradation assays revealed that hPNPaseOLD-35 degraded c-myc mRNA. Overexpression of Myc partially but significantly protected HO-1 cells from Ad.hPNPaseold-35-induced growth arrest, indicating that Myc down-regulation might directly mediate the growth-inhibitory properties of Ad.hPNPaseold-35. Inhibition of hPNPaseold-35 by an antisense approach provided partial but significant protection against interferon-β-mediated growth inhibition, thus demonstrating the biological significance of hPNPaseold-35 in interferon action. Terminal differentiation and senescence share several common properties, including irreversible cessation of growth and changes in gene expression profiles. To identify molecules that converge in both processes, an overlapping pathway screening was employed that identified old-35, which is human polynucleotide phosphorylase (hPNPaseold-35), a 3′,5′-exoribonuclease. We previously demonstrated that hPNPaseold-35 is a type I interferon-inducible gene that is also induced in senescent fibroblasts. In vitro RNA degradation assays confirmed its exoribonuclease properties, and overexpression of hPNPaseold-35 resulted in growth suppression in HO-1 human melanoma cells. The present study examined the molecular mechanism of the growth-arresting property of hPNPaseold-35. When overexpressed by means of a replication-incompetent adenoviral vector (Ad.hPNPaseold-35), hPNPaseold-35 inhibited cell growth in all cell lines tested. Analysis of cell cycle revealed that infection of HO-1 cells with Ad.hPNPaseold-35 resulted in arrest in the G1 phase and eventually apoptosis accompanied by marked reduction in the S phase. Infection with Ad.hPNPaseold-35 resulted in reduction in expression of the c-myc mRNA and Myc protein and modulated the expression of proteins regulating G1 checkpoint and apoptosis. In vitro mRNA degradation assays revealed that hPNPaseOLD-35 degraded c-myc mRNA. Overexpression of Myc partially but significantly protected HO-1 cells from Ad.hPNPaseold-35-induced growth arrest, indicating that Myc down-regulation might directly mediate the growth-inhibitory properties of Ad.hPNPaseold-35. Inhibition of hPNPaseold-35 by an antisense approach provided partial but significant protection against interferon-β-mediated growth inhibition, thus demonstrating the biological significance of hPNPaseold-35 in interferon action. There are two contrasting endpoints in the life of a replicating cell. One involves the normal physiological processes of differentiation or senescence. The other is the pathological process of neoplastic transformation characterized by uncontrolled proliferation and de-differentiation. Treatment of HO-1 metastatic human melanoma cells with fibroblast interferon (IFN-β) 1The abbreviations used are: IFN, interferon; MEZ, mezerein; m.o.i., multiplicity of infection; pfu, plaque-forming unit(s); AS, antisense; HA, hemagglutinin; CDK, cyclin-dependent kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; Rb, retinoblastoma; GAPDH, glyceradehyde-3-phosphate dehydrogenase. and the protein kinase C activator mezerein (MEZ) induces irreversible growth arrest and terminal differentiation characterized by changes in cell morphology, increase in melanin synthesis, modifications in gene expression, and alterations in surface antigen expression (1Fisher P.B. Grant S. Pharmacol. Ther. 1985; 27: 143-166Google Scholar, 2Fisher P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 3Graham G.M. Guarini L. Moulton T.A. Datta S. Ferrone S. Giacomini P. Kerbel R.S. Fisher P.B. Cancer Immunol. Immunother. 1991; 32: 382-390Google Scholar, 4Guarini L. Graham G.M. Jiang H. Ferrone S. Zucker S. Fisher P.B. Pigment Cell Res. Suppl. 1992; 2: 123-131Google Scholar, 5Jiang H. Su Z.Z. Boyd J. Fisher P.B. Mol. Cell Differ. 1993; 1: 41-66Google Scholar). Replicative or cellular senescence, a process leading to irreversible arrest of cell division, was first described in cultures of human fibroblasts that lost the ability to divide upon continuous subcultures (6Hayflick L. N. Engl. J. Med. 1976; 295: 1302-1308Google Scholar). Replicative senescence can result from telomere shortening linked with a DNA end-replication problem, overexpression of certain oncogenes, or tumor suppressor genes, or it can be stress-induced premature senescence after exposure to a variety of oxidative stresses or DNA damaging agents (for a review, see Ref. 7Serrano M. Blasco M.A. Curr. Opin. Cell Biol. 2001; 13: 748-753Google Scholar). Terminal differentiation and cellular senescence share several common traits including irreversible growth arrest and changes in gene expression profiles. To understand the molecular and biochemical basis of the complex physiological changes associated with these phenomena, an overlapping pathway screen was used to identify genes displaying coordinated expression as a consequence of both processes (8Leszczyniecka M. Kang D.-C. Sarkar D. Su Z.Z. Holmes M. Valerie K. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16636-16641Google Scholar). A temporally spaced terminally differentiated human melanoma subtracted cDNA library was screened with cDNAs derived from senescent progeroid fibroblast cells. This led to the identification of old-35, which is human polynucleotide phosphorylase (hPNPaseold-35), a 3′,5′ exoribonuclease involved in RNA degradation (8Leszczyniecka M. Kang D.-C. Sarkar D. Su Z.Z. Holmes M. Valerie K. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16636-16641Google Scholar). hPNPaseold-35 is a highly evolutionary conserved gene in plants, prokaryotes and eukaryotes having similar domain structure and functional properties in all species. In vitro assays confirmed that hPNPaseold-35 is involved in RNA degradation. Analysis of the expression profile of hPNPaseold-35 revealed that it is predominantly a type I interferon-inducible gene, and its expression is also induced in senescent fibroblasts in comparison with young fibroblasts. These findings indicate that hPNPaseold-35 might play an essential role in interferon- and senescence-induced growth arrest. Indeed, when hPNPaseold-35 is transfected by plasmid or transduced via a replication-incompetent adenovirus (Ad.hPNPaseold-35), there is a marked reduction in the colony-forming ability of HO-1 cells. The objective of the present study was to elucidate the molecular mechanism of the growth-suppressing property of Ad.hPNPaseold-35. The protooncogene c-myc is involved in a wide range of cellular processes including proliferation, differentiation, and tumorigenesis (for a recent review, see Ref. 9Grandori C. Cowley S.M. James L.P. Eisenman R.N. Annu. Rev. Cell Dev. Biol. 2000; 16: 653-699Google Scholar). Myc belongs to the Max network, a group of transcription factors containing basic helix-loop-helix zipper motifs (10Ferre-D'Amare A.R. Pognonec P. Roeder R.G. Burley S.K. EMBO J. 1994; 13: 180-189Google Scholar, 11Murre C. McCaw P.S. Vaessin H. Caudy M. Jan L.Y. Jan Y.N. Cabrera C.V. Buskin J.N. Hauschka S.D. Lassar A.B. et al.Cell. 1989; 58: 537-544Google Scholar). Myc heterodimerizes with Max and binds to the E-box sequence (CACGTG), thereby activating transcription (12Blackwood E.M. Eisenman R.N. Science. 1991; 251: 1211-1217Google Scholar). Max is constitutively expressed throughout the cell cycle (13Blackwood E.M. Luscher B. Eisenman R.N. Genes Dev. 1992; 6: 71-80Google Scholar), and it also heterodimerizes with the Mad family of transcription factors: Mad1, Mxi1, Mad3, and Mad4 (14Ayer D.E. Eisenman R.N. Genes Dev. 1993; 7: 2110-2119Google Scholar, 15Zervos A.S. Gyuris J. Brent R. Cell. 1993; 72: 223-232Google Scholar, 16Hurlin P.J. Queva C. Koskinen P.J. Steingrimsson E. Ayer D.E. Copeland N.G. Jenkins N.A. Eisenman R.N. EMBO J. 1995; 14: 5646-5659Google Scholar); however, in contrast to Myc-Max, the Mad-Max heterodimers act as transcriptional repressors at the same The of Myc is its essential role in cell of Myc in fibroblasts S phase and G1 phase of the cell of a Myc is to cells the cell cycle M. D. 1989; Scholar, J. S.M. 1989; Scholar). The of cell cycle the G1 phase is also by the of the cyclin-dependent kinase and and the of these are inhibited by the including and and the of family including and J. J. Curr. Opin. Cell Biol. 2001; 13: Scholar). and are essential in cells and when overexpressed are to the G1 J. M. Genes Dev. 1993; 7: Scholar, D. M. H. Mol. Cell. Biol. 1994; 14: Scholar). The pathway by which Myc induces cell cycle is by activating and C. K. A. R. J. S. P. J. M. EMBO J. Scholar, A. H. 14: Scholar, H. C. M. C.V. D. B. Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar, C. P. Eisenman R.N. Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar). consequence of the by Myc of is its of and of the complex M. M. Scholar). and result in of the This to of a family of transcription factors that a of genes cell cycle from with and with the of by to cell cycle R. K. Mol. Cell. Biol. Scholar). In Myc can directly and transcription J. M. M. M. S. R. L.P. 2001; Scholar, Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar). In the present that infection of HO-1 melanoma cells with in cell cycle arrest in the G1 phase and eventually apoptosis with marked reduction in DNA reduction in expression of the c-myc mRNA and Myc protein that was accompanied by of Overexpression of Myc protected HO-1 cells against cell These findings that Myc might play a role in the growth-inhibitory properties of Ad.hPNPaseold-35. We also that of hPNPaseold-35 by an antisense partially but significantly HO-1 cells from interferon-β-mediated growth inhibition, thereby a role of hPNPaseold-35 in interferon action. Cell and Cell human growth and growth phase human and and metastatic melanoma cell lines and cells as previously described Su Z.Z. S. Fisher P.B. 2002; Scholar). and cell lines by of HO-1 cells with or antisense hPNPaseold-35 and with and cell lines by of HO-1 cells with and expression provided by C. and with Cell growth and cell by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium as described Su Z.Z. S. Fisher P.B. 2002; Scholar). with and mezerein to cell and Infection and of hPNPaseold-35 adenovirus described previously (8Leszczyniecka M. Kang D.-C. Sarkar D. Su Z.Z. Holmes M. Valerie K. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16636-16641Google Scholar, K. S. and Scholar). A similar was employed to an antisense hPNPaseold-35 adenovirus The adenoviral vector was used as a as previously described Su Z.Z. S. Fisher P.B. 2002; Scholar). and hPNPaseold-35 was by the and The of the was by and it was the of to was by hPNPaseold-35 in an antisense of The c-myc expression plasmid P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 3Graham G.M. Guarini L. Moulton T.A. Datta S. Ferrone S. Giacomini P. Kerbel R.S. Fisher P.B. Cancer Immunol. Immunother. 1991; 32: 382-390Google was provided by HO-1 cells at a of and transfected with of vector or P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 3Graham G.M. Guarini L. Moulton T.A. Datta S. Ferrone S. Giacomini P. Kerbel R.S. Fisher P.B. Cancer Immunol. Immunother. 1991; 32: 382-390Google to the from the the cells with Ad.hPNPaseold-35 at a multiplicity of infection of or the cells and and cells in after assays in HO-1 cells as described E. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: Scholar). RNA and RNA was from the cells to the from the and was as described D. Su Z.Z. M. Valerie K. P. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: Scholar). The cDNA used a from human a from a from human human and human In and in mRNA vitro was the the as a expression and to the from the of RNA from HO-1 cells with of in vitro protein at from to The RNA was the and was D. Su Z.Z. M. Valerie K. P. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: Scholar). was as previously described D. Su Z.Z. M. Valerie K. P. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: Scholar). cells in containing and and at at The was used as cell of cell used and to a The Myc Max and from and A and provided by C. and cells at a of cells in of a The the cells with Ad.hPNPaseold-35 at an of or the cells with The cells with and with of at by and with of and in a Cell in and at in The cells with A at and with Cell cycle was a and cells with or Ad.hPNPaseold-35 or or with fibroblast and assays as described previously S. 2001; Scholar). protein of cell and of protein used the process in which to the of the These by and the and to the The via the to a with an against that is to and the The was by the of the at a of a was of by protected significant demonstrated that infection with Ad.hPNPaseold-35 inhibited in HO-1 melanoma cells (8Leszczyniecka M. Kang D.-C. Sarkar D. Su Z.Z. Holmes M. Valerie K. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16636-16641Google Scholar). The present to the molecular mechanism the growth-arresting property of Ad.hPNPaseold-35. melanoma cell lines and human with and the growth of the cells was by in infection with Ad.hPNPaseold-35 resulted in significant growth in all of the cells. The growth-inhibitory significant from after in certain cell lines and infection with Ad.hPNPaseold-35 inhibited cell In Ad.hPNPaseold-35 infection inhibited the growth of other cell including and and of or To the mechanism of growth inhibition, cell cycle was Ad.hPNPaseold-35 infection in HO-1 cells. When the cells with Ad.hPNPaseold-35 at a of there was a significant increase in of cells indicating apoptosis and a in the S phase indicating of DNA A and When the of was by cells at a of there was an significant increase in cells in the G1 phase of the cell cycle C and at and after This increase was also accompanied by a marked in the S phase. the cells with but or to by apoptosis The of cell was when HO-1 cells with Ad.hPNPaseold-35 at a is that at of the cells are with adenovirus these it might be that infection with Ad.hPNPaseold-35 induces cell cycle arrest at the G1 phase that in apoptosis. The of DNA Ad.hPNPaseold-35 infection was confirmed a in infection with an DNA Infection with Ad.hPNPaseold-35 DNA by at an of and by at after is in both terminal differentiation and senescence. in in a to when HO-1 cells with to This in the of irreversible growth arrest and terminal differentiation in HO-1 melanoma cells P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 5Jiang H. Su Z.Z. Boyd J. Fisher P.B. Mol. Cell Differ. 1993; 1: 41-66Google Scholar). these was also Ad.hPNPaseold-35 in infection with Ad.hPNPaseold-35 at an of but with inhibited by at after One of the factors that the S phase of the cell cycle is terminal differentiation of melanoma c-myc mRNA expression is H. J. S.M. S. Fisher P.B. 1995; Scholar). The expression of c-myc mRNA Ad.hPNPaseold-35 infection by The expression of c-myc mRNA after Ad.hPNPaseold-35 infection but in or cells at after infection This with the expression of hPNPaseold-35 mRNA that was also after be hPNPaseold-35 mRNA is in HO-1 cells. The expression of the gene Ad.hPNPaseold-35 of Myc protein by is accompanied by of Mad1, the transcriptional to the Max family of transcription factors C. Cowley S.M. James L.P. Eisenman R.N. Annu. Rev. Cell Dev. Biol. 2000; 16: 653-699Google Scholar). In the of its and by Ad.hPNPaseold-35 from Myc expression after Ad.hPNPaseold-35 infection but in or cells at after infection This down-regulation was accompanied by of The of Max protein indicating that infection with Ad.hPNPaseold-35 the transcriptional activator to transcriptional The expression of the gene We c-myc overexpression HO-1 cells from cell first the Myc expression plasmid the cells used in these cells is of expressed protein by in of P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 3Graham G.M. Guarini L. Moulton T.A. Datta S. Ferrone S. Giacomini P. Kerbel R.S. Fisher P.B. Cancer Immunol. Immunother. 1991; 32: 382-390Google in cells resulted in significant overexpression of Myc in comparison with the cells transfected with protection HO-1 cells transfected with P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 3Graham G.M. Guarini L. Moulton T.A. Datta S. Ferrone S. Giacomini P. Kerbel R.S. Fisher P.B. Cancer Immunol. Immunother. 1991; 32: 382-390Google Scholar), with and the growth of the cells by Overexpression of Myc provided partial but significant protection against cell and with the that pathway by which Ad.hPNPaseold-35 induces growth suppression and cell is by down-regulation of hPNPaseold-35 is a to it can directly c-myc mRNA. a was The of the was first confirmed by it cells. in a protein of in in the cells. To functional to HO-1 cells transfected with and cell growth was by in overexpression of colony-forming ability by indicating that also growth-suppressing that functional was used to in vitro The of hPNPaseOLD-35 protein c-myc mRNA was by in vitro mRNA degradation in with in vitro hPNPaseOLD-35 resulted in degradation of c-myc mRNA. This was c-myc the the gene, cell growth gene and gene This was also hPNPaseOLD-35 with in vitro a transcription result in mRNA degradation. Ad.hPNPaseold-35 infection the S phase of the cell the expression of the of G1 to S was This checkpoint is by Ad.hPNPaseold-35 infection resulted in of and the of was The expression of be in these which is a result of the that a of in the The expression of upon Ad.hPNPaseold-35 There was a significant in the of of Rb, and Ad.hPNPaseold-35 infection when with or cells at after The expression of the gene The that was the biological significance of the growth arrest by hPNPaseold-35. hPNPaseold-35 is induced terminal differentiation by and MEZ, employed an antisense approach to the role of hPNPaseold-35 in the growth arrest associated with with MEZ, or was and HO-1 cells transfected with by infection with The expression of was in the cell by in be in the cells infection with at an of or resulted in marked reduction of and that the expression of We a cell in the HO-1 that and cells with at an of and and after the cells with or MEZ, or in Cell was after be that HO-1 cells are to and a of is to growth P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 5Jiang H. Su Z.Z. Boyd J. Fisher P.B. Mol. Cell Differ. 1993; 1: 41-66Google Scholar). Infection with provided but significant protection against growth both in and in in a and in with cell by in In with at an of and in cell was by by and When cells with at an of the cell was by A of and cell of by This was partially in cells with at an of and in the reduction in cell was and In cells with at an of the reduction in cell was The antisense approach protection against growth arrest at an of of of adenovirus an was employed in these These indicate as a predominantly type I interferon-inducible gene, hPNPaseold-35 might be involved in growth arrest induced by The that infection of in cells provided protection that the of antisense molecules might the of protection from growth Ad.hPNPaseold-35 infection induces apoptosis in HO-1 the of Ad.hPNPaseold-35 infection the expression of and genes Infection with Ad.hPNPaseold-35 resulted in down-regulation of the protein The expression of the protein and protein HO-1 cell lines or and these cell lines with Ad.hPNPaseold-35. in overexpression of but provided partial protection against Ad.hPNPaseold-35-induced cell The molecular mechanism by which Ad.hPNPaseold-35 induces growth arrest to that terminal differentiation and senescence. The Max of transcription factors in cell cycle arrest Myc terminal differentiation of cell and expression of Myc or terminal differentiation of and cells Mol. Cell. Biol. 1991; Scholar, Scholar, L. H. S. Mol. Cell. Biol. 1989; Scholar, M. U. B. K. Proc. Natl. Acad. Sci. U. S. A. Scholar). Inhibition of Myc is to and cells terminal of of the Myc in and of senescence in fibroblasts C. Cell Res. Scholar). the from an to a differentiated there is a from to Mad-Max that as transcriptional Overexpression of the Mad family transcription factors and cells in the G1 phase of the cell cycle and differentiation of cell J. N. Med. 1995; 1: Scholar, Eisenman R.N. Ayer D.E. Mol. Cell. Biol. 16: Scholar, S. Mol. Cell. Biol. Scholar). There is an of the Max and the The expression of both and are differentiation P. R. H. Jr., A. Genes Dev. Scholar, P.J. D. M. Cell Differ. Scholar, E.M. J. M. A. T.A. Dev. Biol. 2000; Scholar, K. 2000; Scholar). differentiated induced by of Cell Res. Scholar). Myc is differentiation as of demonstrated that and to terminal differentiation of and to Myc expression and Eisenman R.N. Mol. Cell. Biol. 2002; Scholar). Overexpression of in human melanoma cells in a proliferation cell cycle and melanin N. K. 2002; Scholar). that Ad.hPNPaseold-35 infection in down-regulation of Myc and of and that overexpression of Myc can from Ad.hPNPaseold-35-induced cell the of the Max in that Ad.hPNPaseold-35 which is also terminal differentiation and senescence 2002; Scholar). the of terminal differentiation in HO-1 cells by was also that human is by S. M. H. M. H. M. Res. 2000; Scholar). down-regulation of Myc can partially the Ad.hPNPaseold-35 There are several of growth arrest in which down-regulation of Myc is associated with of G1 arrest of human cells in down-regulation of Myc and and of A. K. 2002; 99: Scholar). When of cells arrest in the G1 phase of the cell cycle 2001; Scholar). This arrest is associated with down-regulation of Myc and of and overexpression of Myc in cells the of cell cycle One of the present study is the of that of in to Ad.hPNPaseold-35 infection in HO-1 cells. both of these are involved in G1 arrest, the of Myc with is that with In to a transcriptional Myc also the of a which the Scholar). it is that the down-regulation of Myc protein the of is a the and of the of is a Myc gene M. Jr., Genes Dev. 2000; 14: Scholar). down-regulation of Myc in by of growth arrest, of in the other of of pathway in are also associated with of and down-regulation of H. J. 2002; Scholar, M. M. J. C. M. J. Biol. 2000; Scholar). In both the of and also We in HO-1 cells the of are associated with in the in protein Ad.hPNPaseold-35 the down-regulation of which of as a result of down-regulation of that both and at the mRNA after Ad.hPNPaseold-35 infection A study the of mRNA and its and Ad.hPNPaseold-35 infection might be to the of there is and In the present study that Ad.hPNPaseold-35 infection induces cell cycle arrest but eventually the cells by apoptosis. Inhibition of c-myc in human melanoma cells by an antisense approach resulted in G1 cell cycle arrest, which was associated with of and of A. C. B. A. 2001; Scholar). These cells eventually and it was that of was directly apoptosis. in to cell cycle overexpression of apoptosis M. P. Cancer Res. Scholar, M. Scholar). Overexpression of can cells from apoptosis M. Scholar). Ad.hPNPaseold-35 infection the of protein in HO-1 however, there was a significant reduction in protein and overexpression of in these cells HO-1 cells from cell and are similar and are upon the cell In in HO-1 melanoma it previously that agents the of protein at a that of protein Su Z.Z. S. Fisher P.B. 2002; Scholar). 3′,5′ or degradation of RNA cellular including the of S the of and the of of P. E. D. Genes Dev. Scholar, P. E. A. M. D. Cell. Scholar, C. J. P. E. D. EMBO J. Scholar, A.R. EMBO J. Scholar). In and 3′,5′ RNA a complex the S. Proc. Natl. Acad. Sci. U. S. A. Scholar, S. A. S. M. J. 2001; 7: Scholar). The several including the the exoribonuclease and an RNA C. Cell. 1994; Scholar, B. Scholar). The and other proteins S. A. S. M. J. 2001; 7: Scholar). In cells is by the which of at all of which or are to exoribonuclease or RNA with proteins as and the domain of the protein P. E. A. M. D. Cell. Scholar, C. E. A. M. D. P. Genes Dev. 13: Scholar). The however, the the of the that it the structure of which P. C. P. B. EMBO 2002; Scholar). the of the human a similar human also R. J. Mol. Biol. 2002; Scholar). the of hPNPaseold-35 in the human it might be that hPNPaseold-35 to a as is by its in growth arrest terminal differentiation and senescence. of hPNPaseold-35 be its in an pathway that might a RNA having growth property and a gene having an E. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: Scholar, H. Kang D. Fisher P.B. Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar). that antisense of hPNPaseold-35 the cells from growth its biological role in interferon action. Terminal differentiation and senescence are two of the by which the human from the of The that hPNPaseold-35 at the of these two physiological processes and induces growth arrest a tumor suppressor role in are to and to the functional properties of hPNPaseold-35. These also indicate gene and its protein can be used in fibroblasts and human are also to the of overexpression of hPNPaseold-35 can a and also differentiation are These be and the processes of terminal differentiation and senescence and the functional these cellular We P.B. Prignoli D.R. Hermo Jr., H. Weinstein I.B. Pestka S. J. Interferon Res. 1985; 5: 11-22Google Scholar, 3Graham G.M. Guarini L. Moulton T.A. Datta S. Ferrone S. Giacomini P. Kerbel R.S. Fisher P.B. Cancer Immunol. Immunother. 1991; 32: 382-390Google and C. the and expression and and
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