Nocodazole-induced p53-dependent c-Jun N-terminal Kinase Activation Reduces Apoptosis in Human Colon Carcinoma HCT116 Cells

Microtubule-interfering agents are widely used in cancer chemotherapy, and prognostic results vary significantly from tumor to tumor, depending on the p53 status. In preliminary experiments, we compared the expression and phosphorylation profiles of more than 100 protein kinases and protein phosphatases in human colorectal carcinoma cell line HCT116 between p53+/+ and p53−/− cells in response to short term nocodazole treatment through application of Kinetworks™ immunoblotting screens. Among the proteins tracked, the regulation of the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 at Thr-183/Tyr-185 was the major difference between p53+/+ and p53−/− cells. With the loss of the p53 gene, the levels of phosphorylation of Ser-63 of c-Jun and Thr-183/Tyr-185 of JNK1/2 in p53−/− cells did not increase as markedly as in p53+/+ cells in response to a 1-h treatment with nocodazole or other microtubule-disrupting drugs such as vinblastine and colchicine. Similar observations were also made in MCF-7 and A549 tumor cells, which were rendered p53-deficient by E6 oncoprotein expression. However, arsenate-induced JNK activation in p53−/− cells was preserved. Inhibition of p53 expression by its antisense oligonucleotide also attenuated nocodazole-induced JNK activation in p53+/+ cells. Surprisingly, cotransfection of p53+/+ cells with dominant negative mutants of JNK isoforms and treatment of p53+/+ cells with the JNK inhibitor SP600125 actually further enhanced apoptosis in p53+/+ cells by up to 2-fold in response to nocodazole. These findings indicate that inhibition of p53-mediated JNK1/2 activity in certain tumor cells could serve to enhance the apoptosis-inducing actions of cancer chemotherapeutic agents that disrupt mitotic spindle function. Microtubule-interfering agents are widely used in cancer chemotherapy, and prognostic results vary significantly from tumor to tumor, depending on the p53 status. In preliminary experiments, we compared the expression and phosphorylation profiles of more than 100 protein kinases and protein phosphatases in human colorectal carcinoma cell line HCT116 between p53+/+ and p53−/− cells in response to short term nocodazole treatment through application of Kinetworks™ immunoblotting screens. Among the proteins tracked, the regulation of the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 at Thr-183/Tyr-185 was the major difference between p53+/+ and p53−/− cells. With the loss of the p53 gene, the levels of phosphorylation of Ser-63 of c-Jun and Thr-183/Tyr-185 of JNK1/2 in p53−/− cells did not increase as markedly as in p53+/+ cells in response to a 1-h treatment with nocodazole or other microtubule-disrupting drugs such as vinblastine and colchicine. Similar observations were also made in MCF-7 and A549 tumor cells, which were rendered p53-deficient by E6 oncoprotein expression. However, arsenate-induced JNK activation in p53−/− cells was preserved. Inhibition of p53 expression by its antisense oligonucleotide also attenuated nocodazole-induced JNK activation in p53+/+ cells. Surprisingly, cotransfection of p53+/+ cells with dominant negative mutants of JNK isoforms and treatment of p53+/+ cells with the JNK inhibitor SP600125 actually further enhanced apoptosis in p53+/+ cells by up to 2-fold in response to nocodazole. These findings indicate that inhibition of p53-mediated JNK1/2 activity in certain tumor cells could serve to enhance the apoptosis-inducing actions of cancer chemotherapeutic agents that disrupt mitotic spindle function. Given the pivotal roles of microtubules in numerous biological processes such as mitotic spindle formation, treatment of cells with nocodazole and other microtubule-interfering agents evokes the activation of stress response pathways, cell cycle arrest, and the induction of apoptosis. This accounts for the extensive use of microtubule-interfering agents in tumor chemotherapy. In recent years, a great deal of effort has been devoted to elucidating the signaling pathways that mediate the biological activities of microtubule-interfering agents (1Gundersen G.G. Cook T.A. Curr. Opin. Cell Biol. 1999; 11: 81-94Crossref PubMed Scopus (361) Google Scholar). The p53 tumor suppressor protein is a short lived transcription factor that serves as a key player in the cellular response to a variety of extra- and intracellular insults, such as DNA damage, oncogenic activation, and microtubule disruption (2Meek D.W. Cell Signal. 1998; 10: 159-166Crossref PubMed Scopus (177) Google Scholar, 3Ryan K.M. Phillips A.C. Vousden K.H. Curr. Opin. Cell Biol. 2001; 13: 332-337Crossref PubMed Scopus (567) Google Scholar). It is known that p53 exerts its function mainly through transcriptional activation of target genes such as the CDK 1The abbreviations used are: CDK, cyclin-dependent kinase; CK, casein kinase; ERK, extracellular signal-regulated kinase; GST, glutathioneS-transferase; HA, hemagglutinin; JNK, c-Jun N-terminal kinase; MAP, mitogen-activated protein; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MKP, MAP kinase phosphatase; PKA, protein kinase A; PKC, protein kinase C; PTP, protein-tyrosine kinase. For additional abbreviations, see TableI 1The abbreviations used are: CDK, cyclin-dependent kinase; CK, casein kinase; ERK, extracellular signal-regulated kinase; GST, glutathioneS-transferase; HA, hemagglutinin; JNK, c-Jun N-terminal kinase; MAP, mitogen-activated protein; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MKP, MAP kinase phosphatase; PKA, protein kinase A; PKC, protein kinase C; PTP, protein-tyrosine kinase. For additional abbreviations, see TableIinhibitor, p21Waf1/Cip1, for arresting the cell cycle and the proapoptotic protein, Bax, for inducing apoptosis (4Miyashita T. Reed J.C. Cell. 1995; 80: 293-299Abstract Full Text PDF PubMed Scopus (301) Google Scholar, 5El Deiry W.S. Curr. Top. Microbiol. Immunol. 1998; 227: 121-137PubMed Google Scholar). Similar to other stresses, microtubule disruption results in an increase of p53 phosphorylation at multiple sites in a drug- and cell-specific manner, with resultant accumulation of transcriptionally active protein (6Sablina A.A. Chumakov P.M. Levine A.J. Kopnin B.P. Oncogene. 2001; 20: 899-909Crossref PubMed Scopus (65) Google Scholar, 7Stewart Z.A. Tang L.J. Pietenpol J.A. Oncogene. 2001; 20: 113-124Crossref PubMed Scopus (59) Google Scholar). Recently, we have demonstrated that nocodazole-induced phosphorylation of p53 at Ser-392, one of its key activating sites, is mediated through direct p38 MAP kinase stimulation of casein kinase 2 (CK2) in the HeLa cervical and HCT116 colon carcinoma cell lines (8Sayed M. Kim S.O. Salh B.S. Issinger O.G. Pelech S.L. J. Biol. Chem. 2000; 275: 16569-16573Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 9Sayed M. Pelech S.L. Wong C. Marotta A. Salh B. Oncogene. 2001; 20: 6994-7005Crossref PubMed Scopus (51) Google Scholar). To explore downstream p53-dependent regulation of signaling proteins in the early response of cells to nocodazole treatment, we applied three of our Kinetworks™ screens to track quantitatively the expressions of 75 protein kinases and 25 protein phosphatases and the states of 31 known phosphorylation sites in these and other phosphoproteins. This was accomplished by comparing the expression and phosphorylation profiles of these proteins in a human colon carcinoma cell line HCT116 p53+/+ and its derivative HCT116 p53−/−, where the p53 gene was disrupted through homologous recombination (10Waldman T. Kinzler K.W. Vogelstein B. Cancer Res. 1995; 55: 5187-5190PubMed Google Scholar, 11Bunz F. Dutriaux A. Lengauer C. Waldman T. Zhou S. Brown J.P. Sedivy J.M. Kinzler K.W. Vogelstein B. Science. 1998; 282: 1497-1501Crossref PubMed Scopus (2505) Google Scholar). Among the known phosphoproteins tracked, the p53-dependent increase in the phosphorylation and activation of the c-Jun N-terminal kinase (JNK) was the only significant difference between p53+/+ and p53−/− cells. Even though JNK is well known to play an important role in coordinating the cellular response to stress by phosphorylating the transcription factors c-Jun and p53 (12Hu M.C.T. Qiu W.R. Wang Y.P. Oncogene. 1997; 15: 2277-2287Crossref PubMed Scopus (106) Google Scholar, 13Buschmann T. Potapova O. Bar-Shira A. Ivanov V.N. Fuchs S.Y. Henderson S. Fried V.A. Minamoto T. Alarcon-Vargas D. Pincus M.R. Cell. Biol. 2001; PubMed Scopus Google is the that a p53-mediated JNK activity has been In we for the of the p53-mediated JNK activity in a response by the stress of microtubule HCT116 p53 and derivative F. Dutriaux A. Lengauer C. Waldman T. Zhou S. Brown J.P. Sedivy J.M. Kinzler K.W. Vogelstein B. Science. 1998; 282: 1497-1501Crossref PubMed Scopus (2505) Google cells were by Vogelstein carcinoma MCF-7 and MCF-7 p53-deficient and human carcinoma A549 and A549 p53-deficient derivative were from of MCF-7 and A549 p53-deficient cell lines are from E6 were in in a at in with and and were from was from The was from was from was from and were from The JNK inhibitor SP600125 was from were from p53 antisense and were by the of of on a The antisense oligonucleotide is to of of the p53 gene, which is in the that is for of p53 T. J. Cancer Res. PubMed Scopus Google Scholar). The were by were with at the from to the The dominant negative was by Cancer and and dominant negative mutants of were from of B. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of HCT116 cells with these were For of DNA or cells in at were with nocodazole. as the cells were by treatment, with cells in the in and in for at three in the cells were in 25 and 25 at for The DNA was a and were with the Cell DNA were as by C. J. S. M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). cell were as M. Pelech S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). cells were with in with 2 and for Cell was by at for at was by the of PubMed Scopus Google Scholar). of cell were on to and with by The were with and were by and For the of and for Kinetworks™ cells were a in the and at for at the was as a The was in with and the was as a Kinetworks™ were on of The Kinetworks™ for 75 protein for 25 protein and for phosphoproteins. The immunoblotting with of from and the application of a of a for the Kinetworks™ at the For JNK kinase JNK was from cell In JNK kinase was as O. M. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). The JNK activity was by phosphorylation of as by kinase activity was as of phosphorylation was by with have a between p53 and of tumor cells to chemotherapeutic drugs W.S. PubMed Scopus Google Scholar, P.M. J. S. M. A. S. A.J. K.W. Cancer Res. 1997; Google Scholar, F. P.M. C. Waldman T. J. Lengauer C. Kinzler K.W. Vogelstein B. J. 1999; PubMed Scopus Google Scholar). The difference in response between with p53 and p53 in by p53-mediated apoptosis K.H. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of HCT116 cells with nocodazole a response in p53+/+ cells than in p53−/− cells. in of an of was more in p53+/+ than in p53−/− cells at with that cells from cell lines were at a nocodazole treatment and However, of these cells were in in the of microtubule of cells than 2 DNA of cells in p53+/+ cells compared with than in p53−/− cells nocodazole treatment To the signaling pathways downstream of p53 which for the difference in apoptosis we an to on signaling proteins that important in the actions of the tumor suppressor protein p53 in response to nocodazole. In preliminary we applied three Kinetworks™ screens to the expression profiles of up to 75 protein kinases and 25 protein as well as the phosphorylation states of 25 of these protein kinases and other known phosphoproteins not from p53+/+ and p53−/− cells with nocodazole for protein kinases isoforms were in the HCT116 cell lines in and were for other protein kinases kinase kinase casein kinase protein cyclin-dependent kinases and kinase protein kinase and not of 75 kinases that by the Kinetworks™ these protein kinases expression of or between the p53+/+ and p53−/− cell lines the or of these cells were In loss of p53 function was with in and in and kinase; in and and in and JNK and have been to have at and of T. S. Science. 1998; 282: PubMed Scopus Google Scholar, B. B. M. PubMed Scopus Google Scholar, J.M. J. 1995; PubMed Scopus Google Scholar). our we that JNK to JNK, and JNK to The difference in the from used in the Kinetworks™ The or of and in the p53−/− cells were the These findings extensive in protein kinase regulation as a function of p53 status. were also in the of the p53+/+ and p53−/− cells to a 1-h to nocodazole. In the p53+/+ cells, nocodazole to in and and and was with in the levels of and and is not to significant of In the p53−/− cells, the nocodazole treatment in PKA, and and and and in and and expression was in the of p53−/− cells in the p53+/+ cells. 25 protein phosphatases that could with the Kinetworks™ were in the HCT116 cell lines and were protein and protein not In the p53−/− cells compared with the p53+/+ cells, were protein levels of and protein and and in the expressions of and protein The of and of in the p53−/− cells of protein-tyrosine in the levels of protein in the p53−/− and p53+/+ cells, and also from of from the in at the p53−/− cells. However, nocodazole treatment also on other protein phosphatases in the HCT116 cell It a increase in and more in p53−/− cells, and expressions of protein and in p53+/+ cells. The extensive p53-dependent in the levels of the protein kinases and protein phosphatases in the HCT116 cells were also by states of phosphorylation of protein kinases as with phosphorylation in the Kinetworks™ and phosphorylation sites in protein kinases were to and of these kinases demonstrated at or in phosphorylation between the p53+/+ and p53−/− cell lines in the of nocodazole to were also p53-dependent in phosphorylation states of protein kinases which In the states of phosphorylation at in in the protein levels of the protein This was for the activating and phosphorylation The of a protein the of the phosphorylation to the of that protein in a the of the protein kinases were not markedly by the p53 or by nocodazole However, were where loss of p53 function was with phosphorylation of protein and the phosphorylation of these kinases could further by nocodazole in the p53+/+ cells, was not in the p53−/− cells. For the phosphorylation of was enhanced in p53−/− cells compared with p53 cells in phosphorylation in protein in phosphorylation of protein in phosphorylation in protein and nocodazole was in p53+/+ cells, not further in p53−/− cells. the phosphorylation of and were in p53−/− cells compared with p53+/+ cells. nocodazole treatment, these of were in p53−/− cells and were enhanced in p53+/+ cells and was a loss of phosphorylation of and in p53−/− cells compared with p53+/+ cells. from the Kinetworks™ was the p53-dependent regulation of JNK and JNK phosphorylation at activation In the p53−/− cells compared with p53+/+ cells, were of the of JNK JNK and JNK phosphorylation nocodazole treatment of the of and JNK, and and JNK in p53+/+ cells, in JNK phosphorylation of the p53−/− cells to nocodazole. These p53 loss of in phosphorylation of JNK with the of nocodazole-induced phosphorylation at these activating sites, that JNK downstream of p53 in a signaling in the HCT116 p53+/+ cells. The of on and its To the results of the Kinetworks™ with to JNK regulation in the HCT116 cell lines in response to we JNK protein and phosphorylation levels by phosphorylation of JNK was with nocodazole in the p53+/+ cells in and was a of expression of JNK in the p53−/− cells nocodazole However, the protein of JNK the of treatment These findings further indicate a loss in the of microtubule-interfering to JNK in p53−/− cells. In with the levels of JNK, the JNK from p53+/+ cells with nocodazole activity in compared with p53−/− the difference nocodazole treatment in these cell lines in JNK phosphorylation was by the activation of the kinase. To further the of nocodazole-induced JNK activation on p53 we the of nocodazole on JNK activity in p53-deficient of other cell MCF-7 and in which p53 function was through expression of E6 MCF-7 p53-deficient cells a of JNK protein MCF-7 cells a increase of JNK compared with p53-deficient in response to nocodazole treatment a of JNK phosphorylation was in A549 cells nocodazole treatment than in A549 p53-deficient cells, JNK protein expression levels and is that the p53-dependent JNK activation nocodazole treatment is not to HCT116 cells. However, of the of other activities of E6 we to on the HCT116 cells. to the p53-dependent JNK activation was a response to microtubule we the of other microtubule-interfering agents and on JNK activity in HCT116 cells. The of JNK phosphorylation in HCT116 p53+/+ cells was treatment with vinblastine and not with not that the p53-dependent JNK activation to the activity of and colchicine. It was that the of significant activation of JNK in p53−/− cells nocodazole treatment from in the JNK signaling in p53−/− cells. To we used a of stress response pathways p38 MAP kinase and JNK, to HCT116 cells. with for the JNK levels in p53−/− cells, not than that in the p53+/+ cells and This that the stress response JNK pathways were in cell lines and were of the p53 status. on these is also to that and nocodazole JNK activity signaling It further the that the of significant activation of JNK in p53−/− cells nocodazole treatment by the of a p53 To explore further the role of p53 for nocodazole-induced JNK activation, we the of the p53 antisense oligonucleotide treatment on JNK activation in p53+/+ cells in response to nocodazole In p53+/+ cells, treatment with an antisense oligonucleotide at the p53 its at and in and at its protein significant difference was between and cells in p53 protein that the of p53 protein was for p53 antisense oligonucleotide treatment to the p53 protein the levels of active JNK in the p53 antisense p53+/+ cells also by and in a was used as an In kinase of JNK further the of JNK activity antisense oligonucleotide treatment on the we that p53 is for JNK activation, and of JNK to mediate the biological activities of nocodazole in HCT116 cells. The phosphorylation and activation of JNK from activity and The levels of and were in HCT116 cell lines and by nocodazole a in nocodazole treatment and an increase with nocodazole treatment in p53−/− cells. was more protein in from p53−/− than from p53+/+ cells, the protein of the of nocodazole treatment However, was a activation by nocodazole of activity in p53+/+ cells the activity of the could not in the p53−/− cells p53 activation of JNK at in through stimulation of Given the roles of JNK with induction of apoptosis in response to microtubule as demonstrated by a of recent J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Wang M. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google an as to the JNK activation in response to nocodazole for the of p53+/+ and p53−/− cells to nocodazole-induced To we p53+/+ cells with dominant negative mutants of JNK and by a 1-h nocodazole treatment to of these could nocodazole-induced apoptosis. significant difference in JNK activation was between cells and cells nocodazole treatment with was on apoptosis induction a nocodazole treatment in the cells with as by However, with dominant negative mutants of JNK p53+/+ cells a in the phosphorylation of JNK nocodazole treatment compared with cells Surprisingly, a increase in the of cells nocodazole treatment was in the p53+/+ cells with dominant negative SP600125 is a JNK inhibitor and significant for to inhibition of phosphorylation of c-Jun and J.C. A. S. S. D.W. S. A. 2001; PubMed Scopus Google Scholar). a short term treatment with nocodazole and SP600125 was we inhibition of JNK and c-Jun phosphorylation in p53+/+ cells in response to a 1-h SP600125 treatment compared with nocodazole only treatment with a of nocodazole and SP600125 for a increase in apoptosis was in HCT116 p53+/+ cells, was SP600125 was used This is with the of JNK activity on apoptosis our observations that the JNK activation by nocodazole treatment is more to than The extensive use of microtubule-interfering agents in chemotherapeutic treatment of a variety of human has a great deal of effort devoted to the signaling pathways that mediate the cellular to microtubule a of signaling pathways through the use of Kinetworks™ we in the levels of expression and phosphorylation of protein kinases and phosphatases in with loss of p53 function and in response to nocodazole treatment and of the roles of these is at to of of these However, the difference in nocodazole which was p53 was for the regulation of p53 and JNK have been to mediate cellular to the actions of microtubule-interfering have been from levels of protein kinases and protein phosphatases and phosphorylation levels of protein kinases in p53+/+ and p53−/− kinase kinase kinase 2 (CK2) p38 kinase kinase kinase kinase signal-regulated kinase signal-regulated kinase 2 signal-regulated kinase signal-regulated kinase kinase kinase kinase kinase kinase kinase 2 factor kinase suppressor of kinase kinase kinase kinase 2 kinase kinase kinase kinase kinase kinase kinase kinase 2 kinase MAP kinase for in for in kinase kinase kinase to phosphorylation sites that are also in to phosphorylation sites that are also in to phosphorylation sites that are also in kinase kinase kinase kinase kinase kinase protein kinase protein kinase protein kinase kinase protein kinase kinase are on the of for target proteins with a and The target proteins were the Kinetworks™ and screens by The phosphorylation sites are on human protein With the of and only the results for protein kinases and protein phosphatases that in of with are were than for these The are for the p53+/+ cells, the other the in the to the and p53+/+ cells. are the of The of these protein screens was for in to phosphorylation sites that are also in in a The are on the of for target proteins with a and The target proteins were the Kinetworks™ and screens by The phosphorylation sites are on human protein With the of and only the results for protein kinases and protein phosphatases that in of with are were than for these The are for the p53+/+ cells, the other the in the to the and p53+/+ cells. are the of The of these protein screens was The of JNK activation on p53 was in three cell lines and p53-deficient in which the p53 function was disrupted through JNK activation was in three cells not in p53-deficient that the p53-dependent JNK activity a response to nocodazole-induced microtubule disruption and is not to a cell In to other agents vinblastine and not could also JNK activation in p53-dependent manner, which that is the of drugs that the p53-dependent JNK The for to The of JNK activation in p53−/− cells could not to in the stress response pathways mediated by JNK was to JNK in of treatment of p53+/+ cells with p53 antisense oligonucleotide that the activation of JNK in response to nocodazole from the difference in the p53 in these cell that the p53 tumor suppressor of This is in to the from that p53 is a downstream of It has been that JNK p53 at and in response to and treatment (12Hu M.C.T. Qiu W.R. Wang Y.P. Oncogene. 1997; 15: 2277-2287Crossref PubMed Scopus (106) Google T. Potapova O. Bar-Shira A. Ivanov V.N. Fuchs S.Y. Henderson S. Fried V.A. Minamoto T. Alarcon-Vargas D. Pincus M.R. Cell. Biol. 2001; PubMed Scopus Google Scholar, D.W. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google to of which in expression of and proapoptotic of such as Similar to our the between p53 and JNK activation has been in and cells However, from a cell lines with p53 Zhou 1999; PubMed Scopus Google Scholar). Even though is p53 JNK activation in response to we have that at in through the activity of the JNK kinase known phosphatases that JNK our preliminary indicate that the p53-mediated JNK activation is of p53 transcriptional activity an inhibitor of p53 transcriptional activity Science. 1998; Scopus Google and S. the JNK activation nocodazole This is not transcriptionally activities of p53 have also been in recent K.M. Phillips A.C. Vousden K.H. Curr. Opin. Cell Biol. 2001; 13: 332-337Crossref PubMed Scopus (567) Google Scholar). It to the signaling that from p53 to JNK by the of dominant negative mutants of of JNK as well as p53 pathways on the p53-dependent JNK is that activation of the JNK signaling pathways is in regulation of apoptosis J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Wang T. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google C. J. A. D. Science. 2000; PubMed Scopus Google Scholar). However, the roles of JNK in or apoptosis and on the cell and the of JNK activation Wang D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Curr. Opin. Cell Biol. 1998; 10: PubMed Scopus Google Scholar). The between response and JNK activation in p53+/+ cells to that the p53-dependent JNK activity for inducing apoptosis in response to nocodazole of dominant negative mutants of JNK isoforms on JNK activity and apoptosis in p53+/+ with nocodazole. This by isoforms of In with cotransfection of p53+/+ cells with dominant negative mutants of JNK1/2 isoforms JNK activation by nocodazole However, to our of an of the we a significant increase in the of cells in cells. The results demonstrated that the p53-dependent JNK activity by nocodazole is in the HCT116 cells. with JNK activity by p53+/+ cells with nocodazole for with a JNK also in an enhanced response compared with with nocodazole our preliminary have that cells dominant negative also apoptosis to is known the the role of JNK in cells from apoptosis has been in on our we a for the role of JNK activity in p53+/+ cells in response to nocodazole Given the important roles of p53 in the cellular response to HCT116 cells with nocodazole a p53-mediated microtubule that is to in p53+/+ than in p53−/− cells. the a certain cells which is mediated by the p53-dependent JNK in an effort to the However, the nocodazole treatment in our in the in of microtubule in p53+/+ cells, which the lines of our observations and of are in of Wang D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that the JNK activation in apoptosis and activation was by the activation Given the of the p53-dependent JNK our a role for the JNK activity in the stress response to nocodazole the roles of a MAP kinase kinase kinase of and its JNK activation, in cell have been by gene disruption in cell line in response to microtubule disruption by nocodazole T. S. Science. 1998; 282: PubMed Scopus Google Scholar). difference in apoptosis was between p53+/+ and p53−/− cells with nocodazole for a to which a role of JNK in cells from apoptosis in p53+/+ The early JNK activation to the of apoptosis the p53-dependent JNK activity as an response to treatment of However, early response the apoptosis signaling is our preliminary observations have that is increase of apoptosis in p53+/+ cells with JNK at nocodazole which is also in with our of JNK was by Potapova O. M. Cell. Biol. 2000; 20: PubMed Scopus Google in HCT116 p53−/− and other p53-deficient cell lines JNK antisense oligonucleotide treatment, which the role of JNK in human tumor cells The observations in the cell line could one the that is the JNK protein in cells that was the of not JNK activity as in our In our the of the cellular response to microtubule It is the that the p53-dependent JNK activity has been and to with cell in stress response to microtubule to the by which the JNK exerts its role also have for cancer microtubule-interfering drugs in are to Vogelstein for HCT116 p53+/+ and p53−/− cell and for JNK Tang for p53 and for

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