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The antiapoptotic DeltaNp73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway.

ABSTRACT: p73, the structural and functional homologue of p53, exists as two major forms: the transactivation-proficient, proapoptotic TAp73 or the transactivation-deficient, antiapoptotic DNp73. Expectedly, expression of both these major forms has to be coordinated precisely to achieve the desired cellular outcome. Genotoxic insults resulting in cell death lead to the stabilization of TAp73, mainly through posttranslational modifications, and the concomitant degradation of DNp73, through poorly understood mechanisms. We have therefore investigated the possible mechanisms of stress-induced DNp73 degradation and show here that c-Jun, the AP-1 family member activated by stress signals and involved in stabilizing TAp73, promotes DNp73 degradation. Genotoxic stress-mediated DNp73 degradation was found to occur in a c-Jun-dependent manner through a ubiquitin-independent but proteasome-dependent mechanism. Absence or down-regulation of c-Jun expression abrogated the reduction of DNp73 levels upon stress insults, whereas overexpression of c-Jun led to its degradation. c-Jun controlled DNp73 degradation through the nonclassical, polyamine-induced antizyme (Az) pathway by regulating the latter's processing during stress response. Consistently, expression of c-Jun or Az, or addition of polyamines, promoted DNp73 degradation, whereas silencing Az expression or inhibiting Az activity in cells exposed to stress reduced c-Jun-dependent DNp73 degradation. Moreover, Az was able to bind to DNp73. These data together demonstrate the existence of a c-Jun-dependent mechanism regulating the abundance of the antiapoptotic DNp73 in response to genotoxic stress.

SUBMITTER: Dulloo I

PROVIDER: S-EPMC2841924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previous studies have shown that at moderate levels of spectral degradation, semantic predictability facilitates language comprehension. It is argued that when speech is degraded, listeners have narrowed expectations about the sentence endings; i.e., semantic prediction may be limited to only most highly predictable sentence completions. The main objectives of this study were to (i) examine whether listeners form narrowed expectations or whether they form predictions across a wide range of probable sentence endings, (ii) assess whether the facilitatory effect of semantic predictability is modulated by perceptual adaptation to degraded speech, and (iii) use and establish a sensitive metric for the measurement of language comprehension. For this, we created 360 German Subject-Verb-Object sentences that varied in semantic predictability of a sentence-final target word in a graded manner (high, medium, and low) and levels of spectral degradation (1, 4, 6, and 8 channels noise-vocoding). These sentences were presented auditorily to two groups: One group (n =48) performed a listening task in an unpredictable channel context in which the degraded speech levels were randomized, while the other group (n =50) performed the task in a predictable channel context in which the degraded speech levels were blocked. The results showed that at 4 channels noise-vocoding, response accuracy was higher in high-predictability sentences than in the medium-predictability sentences, which in turn was higher than in the low-predictability sentences. This suggests that, in contrast to the narrowed expectations view, comprehension of moderately degraded speech, ranging from low- to high- including medium-predictability sentences, is facilitated in a graded manner; listeners probabilistically preactivate upcoming words from a wide range of semantic space, not limiting only to highly probable sentence endings. Additionally, in both channel contexts, we did not observe learning effects; i.e., response accuracy did not increase over the course of experiment, and response accuracy was higher in the predictable than in the unpredictable channel context. We speculate from these observations that when there is no trial-by-trial variation of the levels of speech degradation, listeners adapt to speech quality at a long timescale; however, when there is a trial-by-trial variation of the high-level semantic feature (e.g., sentence predictability), listeners do not adapt to low-level perceptual property (e.g., speech quality) at a short timescale.

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The antiapoptotic DeltaNp73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway.

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