Rôle des MAPK dans les rythmes biologiques des noyaux suprachiasmatiques et des oscillateurs périphériques
CHANSARD, Mathieu (2007) Rôle des MAPK dans les rythmes biologiques des noyaux suprachiasmatiques et des oscillateurs périphériques. Thèses de doctorat, Université Louis Pasteur.
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Most living organisms have developed endogenous biological clocks to adapt to and anticipate daily and seasonal changes in the environment. In mammals, a main circadian clock is located within the suprachiasmatic nuclei (SCN) of the hypothalamus, and multiple oscillators exist in the periphery. Autoregulatory feedback loops, where clock proteins regulate their own rhythmic expression by inhibiting the transcription of their cognate genes, constitute the circadian molecular machinery. At the level of the SCN, an afferent system conveys the light information to the SCN to entrain the clock to 24 h, while efferent systems, including the synthesis of the pineal melatonin hormone, distribute the time information to the whole organism. Transcriptional and posttranslational regulations are critical to define the 24-h period of the molecular clockwork, and to regulate the arylalkylamine N-acetyltransferase, a key enzyme for the melatonin synthesis. Recent studies have suggest that two subfamilies of mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase 1/2 and p38MAPK, are involved in these transcriptional and post-translational regulations by phosphorylating target proteins. Little is known on the role of a third subfamily of MAPK, JNK, in the circadian system. The aim of this thesis was to investigate the potential regulatory functions of JNK isoforms in both the molecular clockwork and the melatonin synthesis. Our results demonstrate that JNK isoforms display distinct activation patterns in rat-1 fibroblasts: p46 kDa and p54 kDa isoforms are both acutely phosphorylated while only p46 kDa phosphorylation level is rhythmic over the circadian cycle. We showed that the activation level of JNK is critical to properly define the period of the clock in rat-1 cells. Also, we found that JNK activation determines the pace of the oscillations in the mouse SCN and some but not all peripheral tissues. In the rat pineal gland, we established that the transient cAMP-induced activation of JNK isoforms is also necessary for the cAMPinduced transcription of several genes including Aa-Nat. Besides, both JNK and p38MAPK activation contribute to the expression of Mkp-1, a MAPK phosphatase. Altogether, our results support a role for JNK isoforms at two levels of the circadian system: the molecular clockwork by regulating the period of the clock, and the efferent system by driving the transcription of enzymes that participate to the melatonin synthesis.
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