Computational Identification of a p38SAPK-Regulated Transcription Factor Network Required for Tumor Cell Quiescence

Abstract

The stress-activated kinase p38 plays key roles in tumor suppression and induction of tumor cell dormancy. However, the mechanisms behind these functions remain poorly understood. Using computational tools, we identified a transcription factor (TF) network regulated by p38A/B and required for human squamous carcinoma cell quiescence in vivo. We found that p38 transcriptionally regulates a core network of 46 genes that includes 16 TFs. Activation of p38 induced the expression of the TFs p53 and BHLHB3, while inhibiting c-Jun and FoxM1 expression. Furthermore, induction of p53 by p38 was dependent on c-Jun down-regulation. Accordingly, RNAi down-regulation of BHLHB3 or p53 interrupted tumor cell quiescence, while down-regulation of c-Jun or FoxM1 or overexpression of BHLHB3 in malignant cells mimicked the onset of quiescence. Our results identify components of the regulatory mechanisms driving p38-induced cancer cell quiescence. These may regulate dormancy of residual disease that usually precedes the onset of metastasis in many cancers.

The diversity of sex steroid action: the role of micro-RNAs and FOXO transcription factors in cycling endometrium and cancer

“…However, these results should be interpreted with caution as decidualising endometrial cells acquire a highly secretory phenotype, suggesting that miRNAs may be produced primarily for export. It should also be observed that several miRNA species can regulate ER and PR expression (Pandey & Picard 2010), and the experimentally validated miRNAs that can control ER expression include miR-18ab, miR-19, miR-22, miR-26ab/1297, miR-181, miR-206 and miR-222/221 (Adam et al 2009, Castellano et al 2009, Pandey & Picard 2009, Di Leva et al 2010. PR expression has also been found to be modulated by miR-181 and miR-26ab/1297 (Castellano et al 2009).…”

Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras–MKK3–p38 to regulate in vitro cellular invasion

“…In this study we have been able to observe FOXM1 to act downstream from RAS-MKK3-p38 and confer invasion and anchorageindependent growth signals. Recently published data demonstrate furthermore, that upregulation of FOXM1 prevents apoptosis and senescence (Park et al, 2009) and may even be downregulated upon induction of dormancy through p38 (Adam et al, 2009). Thus, FOXM1 may serve as a therapeutic target to eliminate those effects of the p38 pathway that support the malignant phenotype, without affecting possible induc- Figure 6 siRNA-mediated knockdown of FoxM1leads to downregulation of p38-dependent invasion, which can be restored by overexpression of FoxM1.…”

ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK

“…40 Previous studies examining transcription factor profile analysis revealed that c-JUN/AP-1 is negatively regulated by p38 phosphorylation. 24,41 In fact, it was found to be reduced in dormant D-HEp3 cells 25 and also in the ERp29-overexpressing MDA-MB-231 cell model. 6 The ERp29-mediated downregulation of basal eIF2a could be due to the inhibition of c-JUN by activation of p38.…”

“…18,24 The mechanistic link between ER stress and tumor cell growth arrest through p38 activation suggests an important role of p38-regulated networks in modulating tumor cell quiescence, survival and apoptosis. 18,24,25 Hence, cells may coordinate growth arrest and survival signals by activating ER stress, leading to resistance to stress-induced death ( Figure 1).…”