Article

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage. Oncogene

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, Switzerland.
Oncogene (Impact Factor: 8.46). 06/2010; 29(24):3554-65. DOI: 10.1038/onc.2010.115
Source: PubMed

ABSTRACT

Protein kinase B (PKB/Akt) is ubiquitously expressed in cells. Phosphorylation of its multiple targets in response to various stimuli, including growth factors or cytokines, promotes cell survival and inhibits apoptosis. PKB is upregulated in many different cancers and a significant amount of the enzyme is present in its activated form. Here we show that PKB phosphorylates one of the anti-apoptotic proteins--transcription factor Twist-1 at Ser42. Cells expressing Twist-1 displayed inefficient p53 upregulation in response to DNA damage induced by gamma-irradiation or the genotoxic drug adriamycin. This influenced the activation of p53 target genes such as p21(Waf1) and Bax and led to aberrant cell-cycle regulation and the inhibition of apoptosis. The impaired induction of these p53 effector molecules is likely to be mediated by PKB-dependent phosphorylation of Twist-1 because, unlike the wild-type mutant, the Twist-1 S42A mutant did not confer cell resistance to DNA damage. Moreover, phosphorylation of Twist-1 at Ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of Twist-1 after promotion of survival during carcinogenesis.

Download full-text

Full-text

Available from: David F Restuccia
  • Source
    • "Hepatocellular carcinoma cells exposure to hypoxic conditions increased HIF-1α expression and induced EMT through a pathway that involves PI3K/Akt[38]. In vivo, high levels of Akt were found to correlate with high levels of Twist1 Ser42 phosphorylation with subsequent decrease of p53 levels and the inhibition of cell cycle arrest and apoptosis[39]. Akt can also regulate EMT through NF-B. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The growing understanding of the molecular mechanisms underlying epithelial-to-mesenchymal transition (EMT) may represent a potential source of clinical markers. Despite EMT drivers have not yet emerged as candidate markers in the clinical setting, their association with established clinical markers may improve their specificity and sensitivity. Mass spectrometry-based platforms allow analyzing multiple samples for the expression of EMT candidate markers, and may help to diagnose diseases or monitor treatment efficiently. This review highlights proteomic approaches applied to elucidate the differences between epithelial and mesenchymal tumors and describes how these can be used for target discovery and validation.
    Full-text · Article · Jan 2016 · EuPA Open Proteomics
  • Source
    • "Thr residues in the HLH region (Firulli et al., 2003; Firulli and Conway, 2008; Vichalkovski et al., 2010; Hong et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Twist proteins (Twist-1 and -2) are highly conserved developmental proteins with key roles for the transcriptional regulation in mesenchymal cell lineages. They belong to the super-family of bHLH proteins and exhibit bi-functional roles as both activators and repressors of gene transcription. The Twist proteins are expressed at low levels in adult tissues but may become abundantly re-expressed in cells undergoing malignant transformation. This observation prompted extensive research on the roles of Twist proteins in cancer progression and metastasis. Very recent studies indicate a novel role for Twist-1 as a potential regulator of adipose tissue (AT) remodeling and inflammation. Several studies suggested that developmental genes are important determinants of obesity, fat distribution and remodeling capacity of different adipose depots. Twist-1 is abundantly and selectively expressed in the adult AT and its constitutive expression is significantly higher in subcutaneous (SAT) vs. visceral (VAT) fat in both mice and humans. Moreover, Twist1 expression is strongly correlated with BMI and insulin resistance in humans. However, the functional roles and transcriptional downstream targets of Twist1 in AT are largely unexplored. The purpose of this review is to highlight the major findings related to Twist1 expression in different fat depots and cellular components of AT and to discuss the potential mechanisms suggesting a role for Twist1 in AT metabolism, inflammation and remodeling.
    Full-text · Article · Aug 2012 · Frontiers in Endocrinology
  • Source
    • "What is remarkable here is that a common targeting mechanism has evolved to control the activity of a core group of functionally linked but structurally diverse factors. Studies in tumor cells have also identified Protein kinase B (PKB/Akt) mediated phosphorylation of Twist-1 at serine 42 as an important means of controlling its activity (Vichalkovski et al., 2010). It will be of interest to examine possible roles for PKB in neural crest development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural crest cells are a population of multipotent stem cell-like progenitors that arise at the neural plate border in vertebrates, migrate extensively, and give rise to diverse derivatives such as melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia. The neural crest gene regulatory network (NC-GRN) includes a number of key factors that are used reiteratively to control multiple steps in the development of neural crest cells, including the acquisition of stem cell attributes. It is therefore essential to understand the mechanisms that control the distinct functions of such reiteratively used factors in different cellular contexts. The context-dependent control of neural crest specification is achieved through combinatorial interaction with other factors, post-transcriptional and post-translational modifications, and the epigenetic status and chromatin state of target genes. Here we review the current understanding of the NC-GRN, including the role of the neural crest specifiers, their links to the control of "stemness," and their dynamic context-dependent regulation during the formation of neural crest progenitors.
    Full-text · Article · Jun 2012 · Developmental Biology
Show more