p38/p53/miR-200a-3p feedback loop promotes oxidative stress-mediated liver cell death
Authors: Weihui Yan
Yi Cao
Ying Wang
Yongtao Xiao
Lina Lu
Wei Lu
Wei Cai
Journal: Cell Cycle (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: 3′-UTR; 3′-untranslated region; ChIP; MAPK; MMP
Affiliations: a Department of Pediatric Surgery ; Xinhua Hospital; School of Medicine; Shanghai Jiao Tong University ; Shanghai , China., Department of Pediatric Surgery; Xinhua Hospital; School of Medicine; Shanghai Jiao Tong University; Shanghai, China, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition; Shanghai, China, Shanghai Institute of Pediatric Research; Shanghai, China

Abstract:  Although our previous studies have provided evidence that oxidative stress has an essential role in total parenteral nutrition (TPN)-associated liver injury, the mechanisms involved are incompletely understood. Here, we show the existence of crosstalk between the miR-200 family of microRNAs and oxidative stress. The members of the miR-200 family are markedly enhanced in hepatic cells by hydrogen peroxide (H2O2) treatment. The upregulation of miR-200-3p in turn modulates the H2O2-mediated oxidative stress response by targeting p38α. The enhanced expression of miR-200-3p mimics p38α deficiency and promotes H2O2-induced cell death. Members of the miR-200 family that are known to inhibit the epithelial to mesenchymal transition (EMT) are induced by the tumor suppressor p53. Here, we show that p53 phosphorylation at Ser 33 contributes to H2O2-induced miR-200s transcription. In addition, we show that p38α can directly phosphorylate p53 at serine 33 upon H2O2 exposure. Thus, we suggest that in liver cells, the oxidative stress-induced, p38α-mediated phosphorylation of p53 at Ser33 is essential for the functional regulation of oxidative stress-induced miR-200 transcription by p53. Collectively, our data indicate that the p53-dependent expression of miR-200a-3p promotes cell death by inhibiting a p38/p53/miR-200 feedback loop. 

Retracted: No

PubPeer comments:
  The specificity of neuronal responses is limited by what is known as the u201caperture problemu201d u2013 if only a single oriented contour of a moving object is in the receptive field (RF), the neuron can only signal motion orthogonal to the orientation of the contour.  An individual grating is perceived as moving orthogonal to its orientation. The above statements are at best misleading and at worst false. As I have noted in several PubPeer comments and a related [blog post] , it is false to imply that the visual system solves the  aperture problem by producing a percept of  contours moving orthogonal to their orientation. The claim is, for example, contradicted by the well-known barberpole illusion. The claim does apply when the aperture is a circle, and from the figures provided, this is the case in question. But - just as in the case of Adelson Movshon (1982), the authors seem to be treating this special case as the general case for the purpose of drawing general conclusions about neural function (as illustrated in the first quote above). Oddly enough, the authors do bring up the barber-pole illusion, saying that the perceptual effects of their  unikinetic plaids  are conceptually similar to barberpole stimuli. In fact, the barberpole illusion, with its simple stripes, is *conceptually* identical to the  individual grating stimuli, not to the  unikinetic stimuli. As such, the perceived motion in the barberpole violates prediction; the stripes do not appear to move in a direction orthogonal to their orientation. **What if the authors were to use, e.g. rectangular apertures to present their  unikinetic stimuli?** Would the outcomes be *as different* as they are when we change the aperture shape from round to rectangular in the case of  individual gratings ? Would the stimuli remain  conceptually similar to the barberpole illusion? Would the neural speculations (at least to the authors satisfaction) still fit? The authors unqualified references to a neuron s  receptive field are also theoretically problematic. The term currently has no theoretical description, as the older conception has long proved invalid and is referred to as  the classical receptive field. De facto definitions may be found in the methods sections of contemporary papers, each set of authors ascertaining its characteristics via multifarious ad hoc procedures. I ve discussed the problems with the concept in other PubPeer posts, including one on the highly-cited Olshausen and Field (1996), and comments linked therein. Wallisch and Movshon cite the Simoncelli and Heeger s (1998)  A model of neuronal responses in visual area MT as a kind of ideal case:  ...few neurons exhibit the idealized pattern of responses that could be expected from the 425 Simoncelli-Heeger model. Simoncelli and Heeger, in their turn, appear to base their model on the same false claim discussed at the beginning of this comment. They cite Adelson and Movshon in the following way:  The V1 neurons described thus far are not selective for stimulus velocity. Rather, they are selective only for the component of velocity orthogonal to their preferred spatial orientation (Adelson Movshon, 1982). Adelson and Movshon (1982) did not come into contact with any neurons; their experiments were psychophysical. Thus Simoncelli-Heeger based their model on a false fact and a mischaracterization of Adelson and Movshon, and, twenty years later, Wallisch and Movshon treat this model as a baseline. ,