Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53 wild CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53 mutant Meg-01 CML cells, but not in BCR-ABL -HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon a-2a (IFNa), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinibinduced TAp73/PML-NB co-localization was accompanied by coimmpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53 mutant and one with p53 wild . A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/ TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinibtreated CML cells. ' UICCKey words: p38 MAPK; pml; p73; nuclear body; chronic myeloid leukemia; imatinib The oncogenic bcr-abl tyrosine kinase resulting from the Philadelphia chromosome (Ph) signals for leukemogenesis of CML. Imatinib mesylate, a specific inhibitor of c-abl and bcr-abl, induces apoptosis of CML cells and has created a revolutionary success in CML treatment. 1 Imatinib down-regulates various antiapoptotic signals including bcl-X L , Akt kinase and NFjB in CML cells. 2 Nevertheless, the proapoptotic mechanism elicited by imatinib has not been well-defined. p53 generally generates an important proapoptotic effect on cells under genotoxic and non-genotoxic stress. However, the p53 level in the imatinib-treated CML cells was reduced and failed to accumulate in response to DNA damage. This is explained by the fact that constitutive phosphorylation of p53 at serine 20 is inhibited by imatinib. 3 Besides, CML cells with wild type p53 are more resistant to imatinib than those lacking p53. 3 Therefore, we rationalized the existence of an imatinib-induced p53-independent proapoptotic mechanism.p73 is a homologue of the p53 tumor suppressor and induces apoptosis by different mechanisms. 4,5 Unlike p53, there are several different isomers of p73 ...
E1B-55kD-deleted adenoviruses have been used as conditionally replicative adenoviruses (CRAds) for therapeutic purposes in tumors with loss-of-function p53 mutation. To target cancer cells that harbor activating mutant KRAS (KRAS aMut ) but spare p53 wild normal cells, we constructed and examined by reporter assays a KRAS aMut but not p53-responsive promoter, the Δp53REP2 promoter. The Δp53REP2 promoter, derived from human double minute 2 (hdm2) P2 promoter with its p53 response elements being deleted, was used to regulate the expression of the hdm2 transgene in a novel E1B-55kD-deleted CRAd, the
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.