The Roles Of JNK In The Oncogenic Growth Of T-ALL Cells

JNK, a subfamily of MAPK superfamily, plays essential roles in regulating various cellular processes, including cell cycle progression, differentiation, apoptosis, and cellular responses to stress. The dysregulation of JNK signaling pathway has been implicated in the occurrence and progression of many diseases such as tumor. The aberrant activity of MAPK superfamily members ERK1/2, JNK, p38, ERK5 etc has been shown to contribute to cell transformation. Furthermore, the subcellualr localization of MAPK superfamily members might also play a role in tumorigenesis. Growing evidence suggests that JNK might be a potential therapeutic target to treat tumors. However, the roles of JNK in tumorigenesis vary according to different cellular context and environment (ie different tumors). Some recent studies even suggest that JNK might play different roles in cellular transformation and oncogenic growth. Therefore, it is of great importance to investigate the roles of JNK in different tumors as well as different stages of tumor progression.T-cell acute lymphoblastic leukemia (T-ALL) is one of the malignant hematopoietic/lymphoid tumors with low morbidity but very poor prognosis. Despite that JNK has been suggested to be a potential therapeutic target to treat various tumors including B lymphoma, it remains largely unknown whether or not JNK is required for the survival and proliferation of T-ALL cells. Thus, it is of both theoretical and pragmatic significance to reveal the roles of JNK in the oncogenic growth of T-ALL cells.In this work, we report that the basal JNK activity contributes to the oncogenic growth of T-ALL cells. Even though JNK is not constitutively activated in T-ALL cells, the aberrant subcellualr localization of JNK protein might facilitate the nuclear accumulation of basal JNK activity, which might play a key role in maintaining the protein levels of c-Myc and Bcl-2. Thus, JNK could be a potential target to treat T-ALL. The experimental details were:1. With eight T-ALL cell lines and two selective JNK inhibitors, we explored the effects of selective blockade of JNK activity in the survival, proliferation, Fas-induced apoptosis of T-ALL cells. Our data suggest that basal JNK activity is required for the oncogenic growth of T-ALL cells.2. Through transfection and selection by G418, we got two Jurkat subclones called Jurkat-CJ1 and Jurkat–CJ2. These two subclones studbly express JNKK2-JNK1 fusion protein, which has constitutive JNK activity. These two subclones showed accelerated proliferation and resistance against Fas-mediated apoptosis. These data confirm that basal JNK activity contributes to the oncogenic growth of T-ALL cells.3. The basal JNK activity in normal T cells is higher than in T-ALL cells. In contrast to the exclusively cytoplasm localization of JNK protein in normal T cells, JNK localizes in both the cytoplasm and the nuclear in T-ALL cells, which is well correlated with the nuclear accumulation of basal JNK activity in T-ALL cells. JNK activity is required to maintain the protein levels of c-Myc and Bcl-2, which contribute to cell cycle pregression and cell survival, respectively.