The Involvement of MAPK Signaling Pathways in Determining the Cellular Response to p53 Activation

The effect of ERK, p38, and JNK signaling on p53-dependent apoptosis and cell cycle arrest was investigated using a Friend murine erythroleukemia virus (FVP)-transformed cell line that expresses a temperature-sensitive p53 allele, DP16.1/p53ts. In response to p53 activation at 32 °C, DP16.1/p53ts cells undergo p53-dependent G1 cell cycle arrest and apoptosis. As a result of viral transformation, these cells express the spleen focus forming env-related glycoprotein gp55, which can bind to the erythropoietin receptor (EPO-R) and mimics many aspects of EPO-induced EPO-R signaling. We demonstrate that ERK, p38 and JNK mitogen-activated protein kinases (MAPKs) are constitutively active in DP16.1/p53ts cells. Constitutive MEK activity contributes to p53-dependent apoptosis and phosphorylation of p53 on serine residue 15. The pro-apoptotic effect of this MAPK kinase signal likely reflects an aberrant Ras proliferative signal arising from FVP-induced viral transformation. Inhibition of MEK alters the p53-dependent cellular response of DP16.1/p53ts from apoptosis to G1 cell cycle arrest, with a concomitant increase in p21WAF1, suggesting that the Ras/MEK pathway may influence the cellular response to p53 activation. p38 and JNK activity in DP16.1/p53ts cells is anti-apoptotic and capable of limiting p53-dependent apoptosis at 32 °C. Moreover, JNK facilitates p53 protein turnover, which could account for the enhanced apoptotic effects of inhibiting this MAPK pathway in DP16.1/p53ts cells. Overall, these data show that intrinsic MAPK signaling pathways, active in transformed cells, can both positively and negatively influence p53-dependent apoptosis, and illustrate their potential to affect cancer therapies aimed at reconstituting or activating p53 function. The effect of ERK, p38, and JNK signaling on p53-dependent apoptosis and cell cycle arrest was investigated using a Friend murine erythroleukemia virus (FVP)-transformed cell line that expresses a temperature-sensitive p53 allele, DP16.1/p53ts. In response to p53 activation at 32 °C, DP16.1/p53ts cells undergo p53-dependent G1 cell cycle arrest and apoptosis. As a result of viral transformation, these cells express the spleen focus forming env-related glycoprotein gp55, which can bind to the erythropoietin receptor (EPO-R) and mimics many aspects of EPO-induced EPO-R signaling. We demonstrate that ERK, p38 and JNK mitogen-activated protein kinases (MAPKs) are constitutively active in DP16.1/p53ts cells. Constitutive MEK activity contributes to p53-dependent apoptosis and phosphorylation of p53 on serine residue 15. The pro-apoptotic effect of this MAPK kinase signal likely reflects an aberrant Ras proliferative signal arising from FVP-induced viral transformation. Inhibition of MEK alters the p53-dependent cellular response of DP16.1/p53ts from apoptosis to G1 cell cycle arrest, with a concomitant increase in p21WAF1, suggesting that the Ras/MEK pathway may influence the cellular response to p53 activation. p38 and JNK activity in DP16.1/p53ts cells is anti-apoptotic and capable of limiting p53-dependent apoptosis at 32 °C. Moreover, JNK facilitates p53 protein turnover, which could account for the enhanced apoptotic effects of inhibiting this MAPK pathway in DP16.1/p53ts cells. Overall, these data show that intrinsic MAPK signaling pathways, active in transformed cells, can both positively and negatively influence p53-dependent apoptosis, and illustrate their potential to affect cancer therapies aimed at reconstituting or activating p53 function. The p53 tumor suppressor protein is activated in response to DNA damage and abnormal proliferative signals and can induce apoptosis through the activation of death-promoting gene targets (e.g. Bax, p53AIP1, Pidd/Lrdd, Puma, and Noxa), and cell cycle arrest through the activation of p21WAF1, GADD45, and 14-3-3σ (1.Benchimol S. Cell Death Differ. 2001; 8: 1049-1051Crossref PubMed Scopus (151) Google Scholar). Apoptosis and arrest are believed to be important mechanisms of p53 tumor suppression, and are capable of preventing the expansion of cancer-prone cells (e.g. harboring mutations and/or under the influence of inappropriate growth signals). The factors and mechanisms underlying the decision to undergo apoptosis or growth arrest in response to p53 are not fully understood. This decision is likely complex and governed by multiple factors that depend on extrinsic factors (e.g. the presence of soluble growth factors) and intrinsic factors (e.g. hyperactive survival signaling pathways, defective death-signaling pathways) that are additionally cell type-specific. We and others have shown that p53-induced apoptosis in hematopoietic cells can be suppressed in the presence of cytokines or mitogenic factors such as phorbol 12-myristate 13-acetate and that cells remain in a viable growth-arrested state (2.Lin Y. Benchimol S. Mol. Cell. Biol. 1995; 15: 6045-6054Crossref PubMed Scopus (76) Google Scholar, 3.Yonish-Rouach E. Resnitzky D. Lotem J. Sachs L. Kimchi A. Oren M. Nature. 1991; 352: 345-347Crossref PubMed Scopus (1995) Google Scholar, 4.Canman C.E. Gilmer T.M. Coutts S.B. Kastan M.B. Genes Dev. 1995; 9: 600-611Crossref PubMed Scopus (400) Google Scholar, 5.Abrahamson J.L. Lee J.M. Bernstein A. Mol. Cell. Biol. 1995; 15: 6953-6960Crossref PubMed Scopus (54) Google Scholar, 6.Quelle F.W. Wang J. Feng J. Wang D. Cleveland J.L. Ihle J.N. Zambetti G.P. Genes Dev. 1998; 12: 1099-1107Crossref PubMed Scopus (94) Google Scholar, 7.Heinrichs S. Deppert W. Oncogene. 2003; 22: 555-571Crossref PubMed Scopus (34) Google Scholar). Survival pathways, commonly activated in transformed cells independently of their normal regulatory signals, can also rescue cells from p53-dependent death. For example, cells with constitutively activated phosphatidylinositol-3′-OH kinase (PI3′K) 2The abbreviations used are: PI3′K, phosphatidylinositol-3′-OH kinase; PKB, protein kinase B; ts, temperature-sensitive; FVP, Friend murine erythroleukemia virus; SFFV, spleen focus-forming virus; EPO, erythropoietin; EPO-R, erythropoietin receptor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; JNK, c-Jun NH2-terminal kinase; 7-AAD, 7-amino-actinomycin D./protein kinase B (PKB) have a delayed response to apoptosis induced by p53 (8.Lin Y. Brown L. Hedley D.W. Barber D.L. Benchimol S. Blood. 2002; 100: 3990-4000Crossref PubMed Scopus (16) Google Scholar, 9.Sabbatini P. McCormick F. J. Biol. Chem. 1999; 274: 24263-24269Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Ectopic expression of anti-apoptotic Bcl-2 proteins in multiple hematopoietic cell lines blocks p53-dependent apoptosis as well as apoptosis induced by γ-irradiation (6.Quelle F.W. Wang J. Feng J. Wang D. Cleveland J.L. Ihle J.N. Zambetti G.P. Genes Dev. 1998; 12: 1099-1107Crossref PubMed Scopus (94) Google Scholar, 10.Chiou S.K. Rao L. White E. Mol. Cell. Biol. 1994; 14: 2556-2563Crossref PubMed Scopus (363) Google Scholar, 11.Schott A.F. Apel I.J. Nunez G. Clarke M.F. Oncogene. 1995; 11: 1389-1394PubMed Google Scholar, 12.Fukunaga-Johnson N. Ryan J.J. Wicha M. Nunez G. Clarke M.F. Carcinogenesis. 1995; 16: 1761-1767Crossref PubMed Scopus (39) Google Scholar, 13.Wang Y. Okan I. Szekely L. Klein G. Wiman K.G. Cell Growth & Differ. 1995; 6: 1071-1075PubMed Google Scholar). These cells remain in a viable p53-dependent growth-arrested state, reminiscent of that observed when p53 is activated in the presence of growth-promoting cytokines (6.Quelle F.W. Wang J. Feng J. Wang D. Cleveland J.L. Ihle J.N. Zambetti G.P. Genes Dev. 1998; 12: 1099-1107Crossref PubMed Scopus (94) Google Scholar, 8.Lin Y. Brown L. Hedley D.W. Barber D.L. Benchimol S. Blood. 2002; 100: 3990-4000Crossref PubMed Scopus (16) Google Scholar, 13.Wang Y. Okan I. Szekely L. Klein G. Wiman K.G. Cell Growth & Differ. 1995; 6: 1071-1075PubMed Google Scholar). Extrinsic and intrinsic survival factors that alter the cellular response to p53 activation are likely to impinge upon targets that inhibit the cell death machinery. Anti-apoptotic Bcl-2 proteins comprise a subset of proteins that function in the mitochondrial apoptotic pathway, inhibiting the action of pro-apoptotic family members that trigger the release of cytochrome c and other apoptogenic factors from the mitochondria, leading to caspase activation and apoptosis (14.Cory S. Adams J.M. Nat. Rev. Cancer. 2002; 2: 647-656Crossref PubMed Scopus (3349) Google Scholar). Under cytokine-stimulated growth and differentiation conditions, the resulting expression of either Bcl-2 or Bcl-XL leads to hematopoietic cell survival (15.Lotem J. Sachs L. Apoptosis. 1999; 4: 187-196Crossref PubMed Scopus (42) Google Scholar). Kinases acting in survival PKB, and protein kinase are to inhibit a pro-apoptotic Bcl-2 family S. Y. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). at by these is by proteins and in the is to Bcl-XL at the J. E. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). a cell line a temperature-sensitive p53 from an erythroleukemia cell line for p53 M. A. N. Bernstein A. Benchimol S. Nature. PubMed Scopus Google Scholar). This cell line was from a with the of the Friend murine erythroleukemia virus a complex of spleen focus-forming virus and Friend murine The of an at a protein that a at and a at 32 °C, the at which p53 is activated and G1 arrest and apoptosis (2.Lin Y. Benchimol S. Mol. Cell. Biol. 1995; 15: 6045-6054Crossref PubMed Scopus (76) Google Scholar, P. S. Benchimol S. Mol. Cell. Biol. PubMed Scopus Google Scholar). As a result of viral transformation, DP16.1/p53ts cells express the env-related glycoprotein P. S. Benchimol S. Mol. Cell. Biol. PubMed Scopus Google Scholar). The potential of from to bind and the erythropoietin receptor many aspects of signaling D. Nature. PubMed Scopus Google Scholar, Blood. PubMed Google the activation of and protein kinase D. A. S.K. J. PubMed Scopus Google Scholar, S.K. J. 1998; PubMed Google Scholar, D. S. J. PubMed Scopus Google Scholar). The is believed to be for the increase in of observed the of P. Benchimol S. 12: Google Scholar, S.K. J. Cell Biol. 1999; PubMed Scopus Google Scholar). an of kinase was as a that to FVP-induced Blood. PubMed Google Scholar, Bernstein A. Nat. 1999; PubMed Scopus Google Scholar). can with to the EPO-R, resulting in kinase activity D. S. J. 2001; PubMed Scopus Google and activation of and signaling in expansion of with Oncogene. 2002; PubMed Scopus Google Scholar). the of p53 the of leading to erythroleukemia M. A. N. Bernstein A. Benchimol S. Nature. PubMed Scopus Google Scholar, F. A. P. Nature. PubMed Scopus Google Scholar). We have shown that the pathway is activated in DP16.1/p53ts cells. is constitutively in these cells, as is pro-apoptotic Moreover, in the presence of phosphorylation of and is and p53-dependent apoptosis is enhanced (8.Lin Y. Brown L. Hedley D.W. Barber D.L. Benchimol S. Blood. 2002; 100: 3990-4000Crossref PubMed Scopus (16) Google Scholar). when p53 is activated in the of an active signaling pathway, to apoptosis is is that other signaling are activated in DP16.1/p53ts cells and that these could also influence the cellular response to p53 activation. In this DP16.1/p53ts cells a to the p53 and that are activated in transformed cells and may cancer cells p53-dependent apoptosis. have the of ERK, p38, and JNK Y. E. Blood. PubMed Google Scholar, Y. N. Blood. 1998; PubMed Google in DP16.1/p53ts cells and investigated their to the cellular response to p53 activation. We show that ERK, p38, and JNK are constitutively active in DP16.1/p53ts cells and that signaling through these MAPK can influence the of p53 to apoptosis. The MEK signal is pro-apoptotic and contributes to p53 activation by phosphorylation on serine residue 15. MEK is the response of DP16.1/p53ts cells to p53 activation is from apoptosis G1 arrest, with a concomitant increase in protein p38 and JNK are and p53-dependent apoptosis when signaling through these kinases is p38 and JNK activated survival in DP16.1/p53ts cells. JNK activity in DP16.1/p53ts cells which could an for the observed increase in p53-dependent apoptosis when JNK signaling is in these cells. This is with other that JNK activity in cells p53 Genes Dev. 1998; 12: PubMed Scopus Google Scholar). Overall, this that intrinsic MAPK signaling pathways, active in transformed cells, can the cellular response to p53 activation and that the Ras/MEK pathway may be a of the decision to undergo p53-dependent apoptosis or G1 Cell DP16.1/p53ts cell line was from the Friend murine erythroleukemia cell line by of a temperature-sensitive p53 at in with and for p53 expression by MAPK and in and to cell to at 32 °C. an of was used at a of Apoptosis and Cell was using and of cells and for and for as For cell cycle cells on in with with for at °C, and in and of data using on a Cell cycle was using of and with was used for cell For the of this additionally and The was used to protein of protein was used for with the of for which was of was to to by to and with the to the p53 and p53 from used to p53 p53 and from Cell was from and was from and also used in this of and and activated is a protein of to a at the S. A. PubMed Scopus Google Scholar). and kinase have and at activating and E. J. S. M. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These by J. was used to kinase expression in with a expression DP16.1/p53ts cells, to the at for a and to and at 32 for or cells by with a and apoptosis was in this was additionally the cell line using to the Inhibition of and DP16.1/p53ts cells using the J. 1995; 14: PubMed Scopus Google Scholar). by with and in to a of of this cell was to of or and to the by the cells to in with and at for to in with to at 32 °C. expression was by and apoptosis was by as of and DP16.1/p53ts cells in the presence or of for at 32 °C. with the for to of and with of protein was with of p53 or for at °C. to the and a at °C, with in an of and by p53 was by with a in DP16.1/p53ts MAPK signaling the cellular response to p53 the activity of ERK, p38, and JNK kinases in DP16.1/p53ts cells. was in DP16.1/p53ts cells under normal growth conditions, and with of the MEK phosphorylation and effect on protein kinase was in DP16.1/p53ts and in cells in the presence of the p38 kinase DP16.1/p53ts cells also which was with of the JNK with effect on of protein These data that ERK, p38, and JNK kinases are constitutively active in DP16.1/p53ts cells and that their signaling are active in DP16.1/p53ts cells under normal growth MEK to p53-dependent MEK activity the cellular response to p53 DP16.1/p53ts cells at 32 in the presence and of MEK as by is as the of cells that for and for p53 activation in apoptosis by and with to a in apoptosis. a that the of apoptosis was at in with cells of DP16.1/p53ts cells with the MEK at effect on cell in the that p53 apoptosis not with a that growth of cells is of D. A. S.K. J. PubMed Scopus Google Scholar). These data that MEK p53-dependent apoptosis in DP16.1/p53ts cells. this the expression of a constitutively activated kinase the effect and enhanced apoptosis of DP16.1/p53ts cells p53 activation at 32 °C. cells a increase in apoptosis at 32 at and in to and cells expression not apoptosis of DP16.1/p53ts cells at °C, that the enhanced apoptotic effect was upon The effect of likely reflects the of active in DP16.1/p53ts cells and is with the that MEK may be fully activated in these cells. The of to signaling was in cells in which cells with cells these data that and MEK can as a in which signaling cells to undergo p53-dependent apoptosis in cells DP16.1/p53ts cells with with or and at or 32 for or and for expression and for apoptosis with and and by Apoptosis is as the of cells that also for and for cells that not cells with the used in A. of the kinase was by with for and protein of p53 at is with p53 and Apoptosis of that p53 on serine in response to to apoptosis D.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. Carcinogenesis. 2001; 22: PubMed Scopus Google Scholar, N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We the phosphorylation of this residue in DP16.1/p53ts cells and that p53 was not at serine at °C, with p53 at this cells at 32 for serine p53 was at either of p53 p53 in DP16.1/p53ts cells at 32 for to when of apoptosis such as the of and phosphorylation upon The of to MEK activity and p53 serine phosphorylation and p53-dependent apoptosis the that Ras/MEK DP16.1/p53ts cells to undergo p53-dependent apoptosis by to p53 phosphorylation at serine 15. is likely that other factors also to p53 serine phosphorylation at 32 °C, serine phosphorylation was not suppressed with a of in p53-dependent apoptosis, to inhibit expression in DP16.1/p53ts cells. of expression in the cells p53-dependent apoptosis was the signal that contributes to p53-dependent apoptosis of DP16.1/p53ts cells is likely through MEK independently of apoptosis is by DP16.1/p53ts cells or with or and for protein expression was by the DP16.1/p53ts cells, the cells at 32 for p53-dependent apoptosis was by and The of cells apoptosis was by and is as the Inhibition of MEK the to p53 p53 DP16.1/p53ts cells undergo a arrest in which is by apoptosis, the the response to p53 activation in these cells. shown that MEK p53-dependent apoptosis, investigated the effect of MEK on p53-dependent cell cycle and DP16.1/p53ts cells at 32 for and cell cycle by and As the of DP16.1/p53ts cells DNA was in the presence of at 32 °C, with the of apoptosis observed with The of cells in of the cell cycle was and the to the of G1 cell cycle cells at 32 for and in the presence of the was with that of cells This arrest response can be to p53 the cell cycle of and cells for at 32 and Moreover, not affect the cell cycle and of DP16.1/p53ts cells at °C, the at which p53 is and MEK the cellular response to p53 the expression of p21WAF1, Puma, and is a of to an important in G1 arrest, and apoptosis. cells not express or at 32 in the presence or of the MEK The of both proteins in DP16.1/p53ts cells p53 activation at 32 °C. In DP16.1/p53ts cells, observed a increase in the of and a in the of with cells p53 activation at 32 °C. under these data that the pathway the cellular response to p53 activation by cells to undergo apoptosis. Moreover, the increase in expression and the in expression upon MEK that MEK activity by Inhibition of p38 and JNK p53-dependent the influence of p38 and JNK MAPK signals on p53-dependent apoptosis, DP16.1/p53ts cells at 32 in the presence of and both p53-dependent apoptosis was effect was observed on cells at 32 or on DP16.1/p53ts cells at these DP16.1/p53ts cells with of and of p38, and of Apoptosis was enhanced in cells the with cells with not in cells the Moreover, of both and in a increase in apoptosis with expression of suggesting that is for activating the anti-apoptotic function of p38 in DP16.1/p53ts cells. increase in apoptosis was observed in DP16.1/p53ts cells not is likely that a JNK MAPK also contributes to JNK activity in DP16.1/p53ts a kinase was not to this Overall, these data demonstrate that intrinsic and signaling p53-dependent apoptosis in DP16.1/p53ts cells. JNK p53 and cells under conditions, JNK to p53 for by the pathway Genes Dev. 1998; 12: PubMed Scopus Google Scholar). We p53 protein in DP16.1/p53ts cells at 32 at leading to the of apoptotic cells and that p53 was with cells the in p53 protein was to an increase in p53 a to the of p53 p53 a of in DP16.1/p53ts cells at 32 °C. In the presence of the p53 to Moreover, an increase in the of serine a with p53 protein was observed in JNK this effect was not observed in cells with the p38 These are with the that JNK p53 in cells Genes Dev. 1998; 12: PubMed Scopus Google and that JNK the pro-apoptotic function of p53 by JNK p53 at the of DP16.1/p53ts cells with the JNK and p53 by and with an The of p53 was in and cells This was and that JNK may p53 at a to is cells undergo apoptosis in response to p53 other cells undergo p53-dependent cell cycle in the cellular response to p53 activation have to extracellular survival factors and to intrinsic factors that in DNA the activation of survival pathways, to apoptosis, the of p53 protein or the of p53 in cell intrinsic and extrinsic factors influence p53-dependent cell cycle arrest and is of in cancer The of cytokines to p53-induced apoptosis and may a by which to (15.Lotem J. Sachs L. Apoptosis. 1999; 4: 187-196Crossref PubMed Scopus (42) Google Scholar). 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These enhanced apoptotic effects that p38 and JNK an anti-apoptotic in DP16.1/p53ts cells and are capable of limiting p53-dependent death. p38 and JNK as in apoptosis, a for these kinases in cell in cells of hematopoietic E. 22: PubMed Scopus Google Scholar, A. 2003; PubMed Scopus Google Scholar). of p53-dependent apoptosis by p38 and JNK in DP16.1/p53ts cells is likely the result of intrinsic kinase activity resulting from activation of the is that other the of FVP-induced to these kinases constitutively is to that the activity of p38 and JNK in this from that which as a result of to cellular JNK was shown to p53 for in cells under conditions, an function to that of JNK activated in response to which leads to p53 phosphorylation and activation Genes Dev. 1998; 12: PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. 1998; PubMed Scopus Google Scholar). the activity of JNK p53 is acting as an anti-apoptotic kinase under and a pro-apoptotic kinase under of cellular this observed an increase in p53 protein in JNK DP16.1/p53ts cells, which was a result of an increase in p53 protein The of JNK to p53 in DP16.1/p53ts cells could account for the enhanced apoptosis observed upon of JNK signaling. Overall, these data that activated MAPK effects on p53 function and cellular MEK MAPK kinase activity contributes to p53-dependent apoptosis in DP16.1/p53ts cells and likely reflects an aberrant Ras proliferative signal arising from FVP-induced viral transformation. Inhibition of this signal at the of MEK alters the p53 cellular response in of G1 arrest apoptosis. intrinsic p38 and JNK MAPK are capable of p53-dependent apoptosis in DP16.1/p53ts cells. JNK is in p53 protein turnover, which could account for the enhanced apoptotic effects of inhibiting this MAPK pathway in DP16.1/p53ts cells. intrinsic MAPK influence p53 function the of cancer therapies aimed at apoptosis either by p53 or by and/or of with We Barber and for and for of the

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