Article

ZEB1 Links p63 and p73 in a Novel Neuronal Survival Pathway Rapidly Induced in Response to Cortical Ischemia

Istituto Dermopatico dell'Immacolata, Italy
PLoS ONE (Impact Factor: 3.53). 02/2009; 4(2):e4373. DOI: 10.1371/journal.pone.0004373
Source: PubMed

ABSTRACT Acute hypoxic/ischemic insults to the forebrain, often resulting in significant cellular loss of the cortical parenchyma, are a major cause of debilitating injury in the industrialized world. A clearer understanding of the pro-death/pro-survival signaling pathways and their downstream targets is critical to the development of therapeutic interventions to mitigate permanent neurological damage.
We demonstrate here that the transcriptional repressor ZEB1, thought to be involved in regulating the timing and spatial boundaries of basic-Helix-Loop-Helix transactivator-mediated neurogenic determination/differentiation programs, functions to link a pro-survival transcriptional cascade rapidly induced in cortical neurons in response to experimentally induced ischemia. Employing histological, tissue culture, and molecular biological read-outs, we show that this novel pro-survival response, initiated through the rapid induction of p63, is mediated ultimately by the transcriptional repression of a pro-apoptotic isoform of p73 by ZEB1. We show further that this phylogenetically conserved pathway is induced as well in the human cortex subjected to episodes of clinically relevant stroke.
The data presented here provide the first evidence that ZEB1 induction is part of a protective response by neurons to ischemia. The stroke-induced increase in ZEB1 mRNA and protein levels in cortical neurons is both developmentally and phylogenetically conserved and may therefore be part of a fundamental cellular response to this insult. Beyond the context of stroke, the finding that ZEB1 is regulated by a member of the p53 family has implications for cell survival in other tissue and cellular environments subjected to ischemia, such as the myocardium and, in particular, tumor masses.

Download full-text

Full-text

Available from: Tong Wen, Jun 30, 2015
0 Followers
 · 
166 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epithelial-Mesenchymal Transition (EMT) is a major cellular process involved at the very fi rst steps of the development. Recent work strongly implicates EMT in cancer progression as well as initiation. The role of EMT during metastatic process has long been controversial since pathologists failed to detect mesenchymal cells in carcinomas. Now, data clearly show the presence of mesenchymal and dedifferentiated cells at the invasive front of some solid tumors. The extra and intracellular signals that lead to EMT are only starting to be understood. Ultimately, every EMTinducing pathway will activate any of the E-cadherin transcriptional repressors (Zeb1, Zeb2, Twist, Snail or Slug). Some of these repressors were found over-expressed in cancer and their expression correlates with the presence of metastases. Recently, studies have implicated the siRNA/ miRNA biogenesis enzyme Dicer in EMT and metastatic progression. Dicer inhibition promotes metastasis while restoring its expression suppresses metastasis. Decreased Dicer expression leads to Zeb1/Zeb2 proteins increased expression and EMT induction. Due to its central role in neuronal regulation cell fate and the importance of miRNA biogenesis in neuronal differentiation, an important direction for future research may involve determining whether Dicer has metastasis-suppressive role in Central Nervous System cancers. Involvement of Epithelial- Mesenchymal Transition in Metastasis A Key
    stem cells and cancer stem cells, Springer Science+Business Media edited by M.A. Hayat, 01/2012: chapter 19: pages 213-229; Springer., ISBN: 978-94-007-2992-6
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ZEB family of transcription factors regulates key factors during embryonic development and cell differentiation but their role in cancer biology has only more recently begun to be recognized. Early evidence showed that ZEB proteins induce an epithelial-to-mesenchymal transition linking their expression with increased aggressiveness and metastasis in mice models and a wide range of primary human carcinomas. Reports over the last few years have found that ZEB proteins also play critical roles in the maintenance of cancer cell stemness, control of replicative senescence, tumor angiogenesis, overcoming of oncogenic addiction and resistance to chemotherapy. These expanding roles in tumorigenesis and tumor progression set ZEB proteins as potential diagnostic, prognostic and therapeutic targets.
    American Journal of Cancer Research 01/2011; 1(7):897-912. · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the zinc finger-homeodomain transcription factor deltaEF1 is implied as a regulatory factor at the crossroad between proliferation and differentiation in carcinogenesis, its potential effect in the regulation of cell cycle progression has not been well elucidated. In our present study, we provide novel finding that, in breast cancer, the ectopic expression of deltaEF1 in MDA-MB-231 cells significantly promoted cell proliferation by increasing the cell number in S phase of the cell cycle. In contrast, deltaEF1 knockdown by RNA interference exhibited an opposite effect, highlighting a potent role of deltaEF1 to promote G1-S transition of breast cancer cells. Moreover, we demonstrated that deltaEF1 down-regulated p21 and concurrently up-regulated the expressions of CDK2 and CDK4 during this process. Further, deltaEF1 inhibited p21 transcription by recruiting to the E(2) box element on the p21 promoter. Depletion of endogenous deltaEF1 in MDA-MB-231 cells was sufficient to allow an inherent release of p21 expression, thus resulting in the cell cycle arrest. In addition, the stimulatory effect of deltaEF1 on cell proliferation through p21 regulation was supported by an inverse correlation of deltaEF1 and p21 expressions observed in both breast cancer cell lines and clinical tumor specimens. Taken together, these observations suggest a dual effect of deltaEF1 in promoting breast cancer cell proliferation, by differentially regulating the cell cycle regulatory proteins.
    Biochimica et Biophysica Acta 12/2009; 1802(2):301-12. DOI:10.1016/j.bbadis.2009.12.002 · 4.66 Impact Factor