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ABSTRACT: Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.
Journal of Biological Chemistry 04/2012; 287(26):22089-98. · 4.77 Impact Factor
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ABSTRACT: The stress kinase mitogen-activated protein kinase kinase 7 (MKK7) is a specific activator of c-Jun N-terminal kinase (JNK), which controls various physiological processes, such as cell proliferation, apoptosis, differentiation, and migration. Here we show that genetic inactivation of MKK7 resulted in an extended period of oscillation in circadian gene expression in mouse embryonic fibroblasts. Exogenous expression in cultured mammalian cells of an MKK7-JNK fusion protein that functions as a constitutively active form of JNK induced phosphorylation of PER2, an essential circadian component. Furthermore, JNK interacted with PER2 at both the exogenous and endogenous levels, and MKK7-mediated JNK activation increased the half-life of PER2 protein by inhibiting its ubiquitination. Notably, the PER2 protein stabilization induced by MKK7-JNK fusion protein reduced the degradation of PER2 induced by casein kinase 1ε. Taken together, our results support a novel function for the stress kinase MKK7 as a regulator of the circadian clock in mammalian cells at steady state.
Journal of Biological Chemistry 01/2012; 287(11):8318-26. · 4.77 Impact Factor
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ABSTRACT: In most species, solar light is both a DNA-damaging agent and the key entraining stimulus for the endogenous circadian clock. The zebrafish is an attractive vertebrate system in which to study the influence of light on gene expression because the DNA repair proteins and circadian oscillators in this species are light-responsive. At the molecular level, light treatment of zebrafish cells induces the production of reactive oxygen species (ROS). ROS both alters the reduction-oxidation (redox) state of these cells and stimulates intracellular extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) cascades that transduce photic signals activating the transcription of particular light-responsive genes, including some clock genes and some DNA repair genes involved in photoreactivation. To date, however, the phototransducing molecules responsible for light-dependent ROS production have not been identified. Flavin-containing oxidases, such as reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, are versatile flavoenzymes that catalyze molecular oxidation in numerous metabolic pathways. Importantly, light induces the photoreduction of the flavin adenine dinucleotide (FAD) moiety in these oxidases, leading to ROS production. Here, we show in cultured zebrafish cells that diphenyleneiodonium chloride (DPI), an inhibitor of NADPH oxidase, both suppresses ERK/MAPK activation and efficiently reduces light-dependent expression of clock and photoreactivation genes. Our results suggest that flavin-containing oxidases may be responsible for light-dependent ROS production and thus light-dependent gene expression in zebrafish. Our findings also support the existence of a regulatory link between photoreactivation and the circadian clock in this species.
Biological & Pharmaceutical Bulletin 01/2011; 34(8):1343-7. · 1.66 Impact Factor
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ABSTRACT: Accumulating evidence highlights intriguing interplays between circadian and metabolic pathways. We show that PER2 directly and specifically represses PPARγ, a nuclear receptor critical in adipogenesis, insulin sensitivity, and inflammatory response. PER2-deficient mice display altered lipid metabolism with drastic reduction of total triacylglycerol and nonesterified fatty acids. PER2 exerts its inhibitory function by blocking PPARγ recruitment to target promoters and thereby transcriptional activation. Whole-genome microarray profiling demonstrates that PER2 dictates the specificity of PPARγ transcriptional activity. Indeed, lack of PER2 results in enhanced adipocyte differentiation of cultured fibroblasts. PER2 targets S112 in PPARγ, a residue whose mutation has been associated with altered lipid metabolism. Lipidomic profiling demonstrates that PER2 is necessary for normal lipid metabolism in white adipocyte tissue. Our findings support a scenario in which PER2 controls the proadipogenic activity of PPARγ by operating as its natural modulator, thereby revealing potential avenues of pharmacological and therapeutic intervention.
Cell metabolism 11/2010; 12(5):509-20. · 17.35 Impact Factor
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Jinzhan Wu,
Junko Kubota, Jun Hirayama,
Yoko Nagai,
Sachiko Nishina,
Tadashi Yokoi,
Yoichi Asaoka,
Jungwon Seo,
Nao Shimizu,
Hiroaki Kajiho,
Takashi Watanabe,
Noriyuki Azuma,
Toshiaki Katada,
Hiroshi Nishina
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ABSTRACT: Many studies have shown that it is possible to use culture conditions to direct the differentiation of murine embryonic stem (ES) cells into a variety of cell types, including cardiomyocytes and neurons. However, the molecular mechanisms that control lineage commitment decisions by ES cells remain poorly understood. In this study, we investigated the role of the 3 major mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38) in ES cell lineage commitment and showed that the p38 MAPK-specific inhibitor SB203580 blocks the spontaneous differentiation of ES cells into cardiomyocytes and instead induces the differentiation of these ES cells into neurons. Robust p38 MAPK activity between embryoid body culture days 3 and 4 is crucial for cardiomyogenesis of ES cells, and specific inhibition of p38 MAPK activity at this time results in ES cell differentiation into neurons rather than cardiomyocytes. At the molecular level, inhibition of p38 MAPK activity suppresses the expression of bmp-2 mRNA, whereas treatment of ES cells with bone morphogenetic protein 2 (BMP-2) inhibits the neurogenesis induced by SB203580. Further, luciferase reporter assays and chromatin immunoprecipitation experiments showed that BMP-2 expression in ES cells is regulated directly by the transcription factor myocyte enhancer factor 2C, a well-known substrate of p38 MAPK. Our findings reveal the molecular mechanism by which p38 MAPK activity in ES cells drives their commitment to differentiate preferentially into cardiomyocytes, and the conditions under which these same cells might develop into neurons.
Stem cells and development 11/2010; 19(11):1723-34. · 4.15 Impact Factor
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Jungwon Seo,
Yoichi Asaoka,
Yoko Nagai, Jun Hirayama,
Tokiwa Yamasaki,
Misako Namae,
Shinya Ohata,
Nao Shimizu,
Takahiro Negishi,
Daiju Kitagawa,
Hisato Kondoh,
Makoto Furutani-Seiki,
Josef M Penninger,
Toshiaki Katada,
Hiroshi Nishina
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ABSTRACT: Stress-induced Sapk/Jnk signaling is involved in cell survival and apoptosis. Recent studies have increased our understanding of the physiological roles of Jnk signaling in embryonic development. However, still unclear is the precise function of Jnk signaling during gastrulation, a critical step in the establishment of the vertebrate body plan. Here we use morpholino-mediated knockdown of the zebrafish orthologs of the Jnk activators Mkk4 and Mkk7 to examine the effect of Jnk signaling abrogation on early vertebrate embryogenesis. Depletion of zebrafish Mkk4b led to abnormal convergent extension (CE) during gastrulation, whereas Mkk7 morphants exhibited defective somitogenesis. Surprisingly, Mkk4b morphants displayed marked upregulation of wnt11, which is the triggering ligand of CE and stimulates Jnk activation via the non-canonical Wnt pathway. Conversely, ectopic activation of Jnk signaling by overexpression of an active form of Mkk4b led to wnt11 downregulation. Mosaic lineage tracing studies revealed that Mkk4b-Jnk signaling suppressed wnt11 expression in a non-cell-autonomous manner. These findings provide the first evidence that wnt11 itself is a downstream target of the Jnk cascade in the non-canonical Wnt pathway. Our work demonstrates that Jnk activation is indispensable for multiple steps during vertebrate body plan formation. Furthermore, non-canonical Wnt signaling may coordinate vertebrate CE movements by triggering Jnk activation that represses the expression of the CE-triggering ligand wnt11.
Journal of Cellular Biochemistry 07/2010; 110(4):1022-37. · 2.87 Impact Factor
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Kentaro Nakagawa,
Misato Sugahara,
Tokiwa Yamasaki,
Hiroaki Kajiho,
Shinya Takahashi, Jun Hirayama,
Yasuhiro Minami,
Yasutaka Ohta,
Toshio Watanabe,
Yutaka Hata,
Toshiaki Katada,
Hiroshi Nishina
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ABSTRACT: SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase) belongs to the MAPK (mitogen-activated protein kinase) family and is important in many biological contexts. JNK activation is regulated by phosphorylation of specific tyrosine and threonine residues sequentially catalysed by MKK4 and MKK7, which are both dual-specificity MAPKKs (MAPK kinases). Previously, we reported that tyrosine-phosphorylation of JNK by MKK4 precedes threonine-phosphorylation by MKK7, and that both are required for synergistic JNK activation. In the present study, we identify the actin-binding protein-280 (Filamin A) as a presumed 'binder' protein that can bind to MKK7, as well as to MKK4, connecting them in close proximity. We show that Filamin family members A, B and C interact with MKK4 and MKK7, but not with JNK. Filamin A binds to an N-terminal region (residues 31-60) present in the MKK7gamma and MKK7beta splice isoforms, but cannot bind to MKK7alpha which lacks these amino acids. This same N-terminal region is crucial for the intracellular co-localization of MKK7gamma with actin stress fibres and Filamin A. Experiments using Filamin-A-deletion mutants revealed that the MKK7-binding region of Filamin A differs from its MKK4-binding region, and that MKK7gamma (but not MKK7alpha) can form a complex with Filamin A and MKK4. Finally, we used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation.
Biochemical Journal 02/2010; 427(2):237-45. · 4.90 Impact Factor
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ABSTRACT: Circadian clocks are intrinsic, time-tracking systems that endow organisms with a survival advantage. Studies of animal models and human tumor samples have revealed that the disruption of circadian rhythms is an important endogenous factor that can contribute to mammalian cancer development. The core of the circadian clock mechanism is a cell-autonomous and self-sustained oscillator system mediated by a transcription/translation-based negative feedback loop that relies on positive and negative elements. Recent studies have implicated these core circadian components in the regulation of both the cell cycle and DNA damage responses (DDR). Indeed, the circadian feedback loop controls the timing of cell proliferation by regulating the expression of key cell cycle genes. Conversely, several intracellular signaling cascades and post-translational modifications that play important roles in the cell cycle and DDR are also essential for circadian clock regulation. Importantly, alteration of a cell's reduction-oxidation (redox) state triggers the transduction of photic signals that regulate circadian clock gene transcription, suggesting that cellular responses to photo-oxidative stress may have been the evolutionary origin of the circadian clock. This review describes selected regulatory aspects of circadian machinery that are evidence of a molecular link between the circadian clock and DDR, focusing particularly on the signaling cascades involved in the light entrainment of the zebrafish circadian clock.
Biological & Pharmaceutical Bulletin 01/2010; 33(4):535-44. · 1.66 Impact Factor
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ABSTRACT: UV radiation causes a number of harmful events including growth delay, cell death and ultimately cancer. The reversal of such effects by concomitant exposure to visible light is a conserved mechanism which has been uncovered in many multi-cellular organisms. Here we show that light-dependent UV-tolerance is a cell autonomous phenomenon in zebrafish. In addition, we provide several lines of evidence indicating that light induction of 64PHR, a DNA repair enzyme, and the subsequent light-dependent DNA repair mediated by this enzyme are prerequisites for light-mediated UV tolerance. 64PHR is evolutionary related to and has a high degree of structural similarity to animal CRY, an essential circadian regulator. The zebrafish circadian clock is controlled by a cell-autonomous and light-dependent oscillator, where zCRY1a functions as an important mediator of light entrainment of the circadian clock. In this study, we show that light directly activates MAPK signaling cascades in zebrafish cells and we provide evidence that light-induced activation of these pathways controls the expression of two evolutionary-related genes, z64Phr and zCry1a, revealing that light-dependent DNA repair and the entrainment of circadian clock share common regulatory pathways.
Cell cycle (Georgetown, Tex.) 10/2009; 8(17):2794-801. · 5.36 Impact Factor
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ABSTRACT: In the vertebrate circadian feedback loop, CLOCK:BMAL heterodimers induce the expression of Cry genes. The CRY proteins in turn inhibit CLOCK:BMAL-mediated transcription closing the negative feedback loop. Four CRYs, which all inhibit CLOCK:BMAL-mediated transcription, exist in zebrafish. Although these zebrafish Crys (zCry1a, 1b, 2a, and 2b) show a circadian pattern of expression, previous studies have indicated that the circadian oscillation of zCry1a could be CLOCK:BMAL-independent. Here we show that abrogation of CLOCK:BMAL-dependent transcription in zebrafish cells by the dominant negative zCLOCK3-DeltaC does not affect the circadian oscillation of zCry1a. Moreover, we provide several lines of evidence indicating that the extracellular signal-regulated kinase (ERK) signaling cascade modulates the circadian expression of zCry1a gene in constant darkness. Taken together, our data strongly support the notion that circadian oscillation of zCry1a is CLOCK:BMAL-independent and further indicate that mechanisms involving non-canonical clock genes could contribute to the circadian expression of zCry1a gene in a cell autonomous manner.
Biological & Pharmaceutical Bulletin 08/2009; 32(7):1183-7. · 1.66 Impact Factor
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ABSTRACT: Clock proteins govern circadian physiology and their function is regulated by various mechanisms. Here we demonstrate that Casein kinase (CK)-2alpha phosphorylates the core circadian regulator BMAL1. Gene silencing of CK2alpha or mutation of the highly conserved CK2-phosphorylation site in BMAL1, Ser90, result in impaired nuclear BMAL1 accumulation and disruption of clock function. Notably, phosphorylation at Ser90 follows a rhythmic pattern. These findings reveal that CK2 is an essential regulator of the mammalian circadian system.
Nature Structural & Molecular Biology 05/2009; 16(4):446-8. · 12.71 Impact Factor
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ABSTRACT: We show for the first time that isoforms of the cAMP response element modulator Crem, regulate the circadian expression of Cyp51 and other cholesterogenic genes in the mouse liver. In the wild type mice the expression of Cyp51, Hmgs, Fpps, and Sqs is minimal between CT12 and CT16 and peaks between CT20 and CT24. Cyp51, Fpps, and Sqs lost the circadian behavior in Crem-/- livers while Hmgcr is phase advanced from CT20 to CT12. This coincides with a phase advance of lathosterol/cholesterol ratio, as detected by GC-MS. Overexpression of CREMtau and ICER has little effect on the Hmgcr proximal promoter while they influence expression from the CYP51 promoter. Our data indicate that Crem-dependent regulation of Cyp51 in the liver results in circadian expression of this gene. We propose that cAMP signaling might generally be involved in the circadian regulation of cholesterol synthesis on the periphery.
Biochemical and Biophysical Research Communications 10/2008; 376(1):206-10. · 2.48 Impact Factor
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ABSTRACT: Circadian rhythms govern a large array of metabolic and physiological functions. The central clock protein CLOCK has HAT properties. It directs acetylation of histone H3 and of its dimerization partner BMAL1 at Lys537, an event essential for circadian function. We show that the HDAC activity of the NAD(+)-dependent SIRT1 enzyme is regulated in a circadian manner, correlating with rhythmic acetylation of BMAL1 and H3 Lys9/Lys14 at circadian promoters. SIRT1 associates with CLOCK and is recruited to the CLOCK:BMAL1 chromatin complex at circadian promoters. Genetic ablation of the Sirt1 gene or pharmacological inhibition of SIRT1 activity lead to disturbances in the circadian cycle and in the acetylation of H3 and BMAL1. Finally, using liver-specific SIRT1 mutant mice we show that SIRT1 contributes to circadian control in vivo. We propose that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock.
Cell 08/2008; 134(2):329-40. · 32.40 Impact Factor
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ABSTRACT: Regulation of circadian physiology relies on the interplay of interconnected transcriptional-translational feedback loops. The CLOCK-BMAL1 complex activates clock-controlled genes, including cryptochromes (Crys), the products of which act as repressors by interacting directly with CLOCK-BMAL1. We have demonstrated that CLOCK possesses intrinsic histone acetyltransferase activity and that this enzymatic function contributes to chromatin-remodelling events implicated in circadian control of gene expression. Here we show that CLOCK also acetylates a non-histone substrate: its own partner, BMAL1, is specifically acetylated on a unique, highly conserved Lys 537 residue. BMAL1 undergoes rhythmic acetylation in mouse liver, with a timing that parallels the downregulation of circadian transcription of clock-controlled genes. BMAL1 acetylation facilitates recruitment of CRY1 to CLOCK-BMAL1, thereby promoting transcriptional repression. Importantly, ectopic expression of a K537R-mutated BMAL1 is not able to rescue circadian rhythmicity in a cellular model of peripheral clock. These findings reveal that the enzymatic interplay between two clock core components is crucial for the circadian machinery.
Nature 01/2008; 450(7172):1086-90. · 36.28 Impact Factor
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ABSTRACT: Light is the key entraining stimulus for the circadian clock, but several features of the signaling pathways that convert the photic signal to clock entrainment remain to be deciphered. Here, we show that light induces the production of hydrogen peroxide (H(2)O(2)) that acts as the second messenger coupling photoreception to the zebrafish circadian clock. Treatment of light-responsive Z3 cells with H(2)O(2) triggers the induction of zCry1a and zPer2 genes and the subsequent circadian oscillation of zPer1. Remarkably, the induction kinetics and oscillation profile in response to H(2)O(2) are identical to those initiated by light. Catalase (Cat), an antioxidant enzyme degrading H(2)O(2), shows an oscillating pattern of expression and activity, antiphasic to zCry1a and zPer2. Interestingly, overexpression of zCAT results in a reduced light-dependent zCry1a and zPer2 gene induction. In contrast, inhibition of zCAT function enhances light-mediated inducibility of these clock genes. These findings implicate the enzymatic function of zCAT enzyme in the negative regulation of light-dependent clock gene transcriptional activation. Our findings provide an attractive link between the regulation of the cellular reduction/oxidation (redox) state and the photic signaling pathways implicated in circadian control.
Proceedings of the National Academy of Sciences 11/2007; 104(40):15747-52. · 9.68 Impact Factor
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ABSTRACT: MAP kinase phosphatase 1 (MKP1) is a negative regulator for the mitogen-activated protein kinase (MAPK)-mediated signal transduction, a key pathway that leads to the regulated expression of circadian clock genes. Here the authors analyzed mkp1 expression by in situ hybridization and found that mkp1 is a light-inducible and clock-controlled gene expressed in the central pacemaker neurons of the hypothalamic SCN. Interestingly, mkp1 presents a marked similarity to the clock core gene per1 in terms of the gene expression profiles as well as the gene promoter organization. Both mkp1 and per1 are subject to bimodal regulation in the SCN: the external light-dependent acute up-regulation and the functional clock-dependent circadian oscillation. Consistent with this, the authors show that mkp1 gene has a per1-like promoter that contains 2 functionally distinct elements: cAMP-responsive element (CRE) and E-box. CRE sites present in the mkp1 promoter constitute the functional binding sites for the CRE binding protein (CREB), which serves as an important regulator that mediates the light-induced signaling cascades in the SCN neurons. Furthermore, the authors show that the E-box present in the mkp1 promoter is necessary and sufficient for transcriptional control exerted by circadian clock core regulators that include a positive complex CLOCK/BMAL1 and a negative factor CRY1. The authors' studies on mkp1 have identified for the first time a gene encoding a phosphatase that functions in light-dependent and time-of-day-dependent manners in the mammalian central clock structure SCN.
Journal of Biological Rhythms 05/2007; 22(2):127-39. · 2.93 Impact Factor
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ABSTRACT: Circadian rhythms govern several fundamental physiological functions in almost all organisms, from prokaryotes to humans. The circadian clocks are intrinsic time-tracking systems with which organisms can anticipate environmental changes and adapt to the appropriate time of day. In mammals, circadian rhythms are generated in pacemaker neurons within the suprachiasmatic nuclei (SCN), a small area of the hypothalamus, and are entrained by environmental cues, principally light. Disruption of these rhythms can profoundly influence human health, being linked to depression, insomnia, jet lag, coronary heart disease and a variety of neurodegenerative disorders. It is now well established that circadian clocks operate via transcriptional feedback autoregulatory loops that involve the products of circadian clock genes. Furthermore, peripheral tissues also contain independent clocks, whose oscillatory function is orchestrated by the SCN. The complex program of gene expression that characterizes circadian physiology involves dynamic changes in chromatin transitions. These remodeling events are therefore of great importance to ensure the proper timing and extent of circadian regulation. How signaling influences chromatin remodeling through histone modifications is therefore highly relevant in the context of circadian oscillation. Recent advances in the field have revealed unexpected links between circadian regulators, chromatin remodeling and cellular metabolism.
Current Opinion in Cell Biology 05/2007; 19(2):230-7. · 12.90 Impact Factor
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ABSTRACT: The Aurora kinases are cell cycle-regulatory serine-threonine kinases that have been implicated in the function of the centrosomes, kinetechores, chromosome dynamics, and cytokinesis. In comparison with other tissues, there are high levels of expression of Aurora-B and -C in testis. What their respective roles in mammalian spermatogenesis are is an open question. Here we describe the expression and distribution patterns of the three kinases in mouse testis using in situ hybridization and immunohistochemistry. Importantly, the localization of Aurora-B is tightly regulated during spermatogenesis, whereas Aurora-C expression appears to be testis specific. To address the function of Aurora-B in spermatogenesis, we have generated transgenic mice using a pachytene-stage-specific promoter driving the expression of either wild-type Aurora-B or an inactive form of the kinase. Expression of the inactive Aurora-B results in abnormal spermatocytes, increased apoptosis, spermatogenic arrest, and subfertility defects. The function of Aurora-C may also be targeted in the Aurora-B transgenic mutants. To address the function of Aurora-C in testis, we generated Aurora-C knockout mice by homologous recombination. Remarkably, Aurora-C null mice were viable, yet the males had compromised fertility. Aurora-C mutant sperm display abnormalities that included heterogenous chromatin condensation, loose acrosomes, and blunted heads. These findings indicate that Aurora-B and Aurora-C serve specialized functions in mammalian spermatogenesis.
Molecular Endocrinology 04/2007; 21(3):726-39. · 4.54 Impact Factor
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ABSTRACT: Disruption of overt circadian rhythms can occur without influencing the endogenous pacemaker, the so-called 'masking' effect classically elicited by light. As the physiological pathways involved in light masking remain elusive, we analyzed mice lacking the dopamine D2 receptor. Although circadian rhythmicity was normal, D2R-null mice showed a markedly deficient light masking response, indicating that D2R-mediated signaling is an essential component of the neuronal pathways leading to light masking of circadian rhythms.
Nature Neuroscience 07/2006; 9(6):732-4. · 15.53 Impact Factor
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ABSTRACT: The molecular machinery that governs circadian rhythmicity comprises proteins whose interplay generates time-specific transcription of clock genes. The role of chromatin remodeling in a physiological setting such as the circadian clock is yet unclear. We show that the protein CLOCK, a central component of the circadian pacemaker, has histone acetyltransferase (HAT) activity. CLOCK shares homology with acetyl-coenzyme A binding motifs within the MYST family of HATs. CLOCK displays high sequence similarity to ACTR, a member of SRC family of HATs, with which it shares also enzymatic specificity for histones H3 and H4. BMAL1, the heterodimerization partner of CLOCK, enhances HAT function. The HAT activity of CLOCK is essential to rescue circadian rhythmicity and activation of clock genes in Clock mutant cells. Identification of CLOCK as a novel type of DNA binding HAT reveals that chromatin remodeling is crucial for the core clock mechanism and identifies unforeseen links between histone acetylation and cellular physiology.
Cell 06/2006; 125(3):497-508. · 32.40 Impact Factor
