Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells

Abstract

Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Here, we report that treatment of T-ALL cells with JNK inhibitors led to cell cycle arrest and apoptosis and increased sensitivity to Fas-mediated apoptosis, whereas weak ectopic expression of MKK7-JNK1 fusion protein, which shows constitutive JNK activity, in T-ALL cells resulted in accelerated cell cycle progression and resistance to Fas-mediated apoptosis. The protein levels of c-Myc and Bcl-2 were reduced in the presence of JNK inhibitors but were enhanced with MKK7-JNK1. Small interfering RNA against JNK1, but not JNK2, exhibited similar effects to JNK inhibitors. These findings suggest that targeting JNK, especially JNK1 isoform, may have some important therapeutic implications in the treatment of T-ALL. Further exploration revealed that JNK protein and basal JNK activity in T-ALL cells showed aberrant subcellular localization, but no hyperactivation of JNK was observed. Thus, our work suggests that there might be novel mechanism(s) other than hyperactivation underlying the protumorigenic role of JNK activity. [Mol Cancer Ther 2009;8(12):3214–22]

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

“…Furthermore, in isolated murine T cells, JNK phosphorylation was inversely associated with Smad4 protein expression (data not shown). Previous studies have indicated that constitutive JNK activity may promote the malignancy of B and T cells (21,31), while mice with a Smad4 deletion were observed to spontaneously develop gastrointestinal cancer (32,33). The possibility that a Smad4 deletion may initiate pancreatic cancer in humans is unclear.…”

“…Smad4 siRNA (Smad4-1, CGA AUA CAC CAA CAA GUA ATT; Smad4-2, AGA UGA AUU GGA UUC UUU ATT), MKP-1 siR NA-1 (GCA UA A CUG CCU UGA UCA A), MK P-1 si R NA-2 (C CA AU U GUC C CA AC C AU U U ) a n d non-targeting control siRNA (scramble, UUC UCC GAA CGU GUC ACG UTT) were purchased from Shanghai GenePharma Co., Ltd. (Shanghai, China). siRNAs that target human JNK1 and JNK2 messenger RNA were designed based on the 1,013-1,031 nt (JNK1) and 461-479 nt (JNK2) sequences, relative to the translation start sites, and were purchased from GE Dharmacon (Lafayette, CO, USA) (21). The JNK siRNA sequences were as follows: 5'-CUG ACA AGC AGU UAG AUGA-3' for JNK1; 5'-CUA GCA ACA UUG UUG UGAA-3' for JNK2.…”

Genotoxic stress-mediated cell cycle activities for the decision of cellular fate

“…36 In unstimulated cells, the basal physiological JNK1 function shows exclusive cytosolic localization. 31,37 By contrast, c-Jun is mostly bound to JNK2, which appears to be responsible for c-Jun ubiquitination and degradation. 29,34 In the cellular response to DNA damage, JNK2 is released from c-Jun, thereby giving more access to active JNK1, resulting in increased JNK1-mediated c-Jun phosphorylation, stability and activity.…”

“…Various stress signals, proinflammatory stimuli, and some mitogenic signals induce JNK activity, which in turn phosphorylates its substrates, such as c-Jun, c-Myc and ATF2, as well as nontranscription factors, such as members of the Bcl-2 family proteins. [29][30][31][32] JNK activation was shown to either induce apoptosis or stimulate After stimulation by tGFβ, smad2 and smad3 (rsmads) become phosphorylated by the activated tGFβ receptor kinases, oligomerize with smad4 forming smad complex (smadC). this complex translocates to the nucleus and regulates the expression of tGFβ target genes with close interaction of FOXO transcription factors, leading p15 and p21-induced cell cycle arrest.…”

Astrocyte Elevated Gene 1 Interacts with Acetyltransferase p300 and c-Jun To Promote Tumor Aggressiveness

“…As the transcriptional hub of multiple upstream oncogenic signals, c-Jun transcription factors have been found to be constitutively activated in many types of tumors (26)(27)(28) and to participate in various processes that promote tumor development and progression, such as angiogenesis and cell survival (29)(30)(31)(32). The essential role of c-Jun in the progression of gliomas has been demonstrated in previous studies (33).…”