scholarly journals MYC-associated factor MAX is an essential regulator of the clock core network

2019 ◽  
Author(s):  
Olga Blaževitš ◽  
Nityanand Bolshette ◽  
Donatella Vecchio ◽  
Ana Guijarro ◽  
Ottavio Croci ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Clock ◽  
Circadian Regulation ◽  
Factor X ◽  
Core Network ◽  
Associated Factor ◽  
Rhythmic Expression ◽  
The Core ◽  
E Box

SummaryThe circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here that the MYC-Associated factor X, MAX, plays a repressive role in this network and operates through its MYC-independent binding to E-box-containing regulatory regions within the promoters of circadian BMAL1 targets. This clock function of MAX is essential for maintaining a proper circadian rhythm but separated by the role of MAX as a partner of MYC in controlling cell proliferation. We also identified MAX Network Transcriptional repressor, MNT, as a fundamental partner of MAX-mediated circadian regulation. Collectively, our data indicate that MAX is an integral part of the core molecular clock and keeps the balance between positive and negative elements of the molecular clock machinery. Accordingly, alteration of MAX transcriptional complexes may contribute to circadian dysfunction in pathological contexts.

scholarly journals MYC-Associated Factor MAX is a Regulator of the Circadian Clock

2020 ◽  
Vol 21 (7) ◽  
pp. 2294
Author(s):  
Olga Blaževitš ◽  
Nityanand Bolshette ◽  
Donatella Vecchio ◽  
Ana Guijarro ◽  
Ottavio Croci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Rhythm ◽  
Clock Gene ◽  
Circadian Regulation ◽  
Factor X ◽  
Associated Factor ◽  
Rhythmic Expression ◽  
Clock Gene Expression ◽  
E Box ◽  
Regulated Promoters

The circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here that the MYC-associated factor X, MAX, plays a repressive role in this network and operates through a MYC-independent binding to E-box-containing regulatory regions within the promoters of circadian BMAL1 targets. We further show that this “clock” function of MAX is required for maintaining a proper circadian rhythm and that MAX and BMAL1 contribute to two temporally alternating transcriptional complexes on clock-regulated promoters. We also identified MAX network transcriptional repressor, MNT, as a fundamental partner of MAX-mediated circadian regulation. Collectively, our data indicate that MAX regulates clock gene expression and contributes to keeping the balance between positive and negative elements of the molecular clock machinery.

scholarly journals The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells

2020 ◽  
Vol 295 (7) ◽  
pp. 2001-2017 ◽  
Author(s):  
M. Carmen Lafita-Navarro ◽  
Judit Liaño-Pons ◽  
Andrea Quintanilla ◽  
Ignacio Varela ◽  
Rosa Blanco ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Transcriptional Regulator ◽  
Bhlh Transcription Factor ◽  
Factor X ◽  
Associated Factor ◽  
Helix Loop Helix ◽  
E Box ◽  
E Boxes ◽  
Cycle Regulation

The MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the basic helix-loop-helix (bHLH) family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E-boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC–MAX dimer activates gene expression. MNT also binds to the MAX dimerization protein MLX (MLX), and MNT–MLX and MNT–MAX dimers co-exist. However, all MNT functions have been attributed to MNT–MAX dimers, and no functions of the MNT–MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT–MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E-boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-sequencing experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT–MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation.

scholarly journals Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2323
Author(s):  
Melissa Witzig ◽  
Amandine Grimm ◽  
Karen Schmitt ◽  
Imane Lejri ◽  
Stephan Frank ◽  
...  
Keyword(s):  
Molecular Clock ◽  
Mitochondrial Dynamics ◽  
Glioma Cells ◽  
Translocator Protein ◽  
Mitochondrial Morphology ◽  
Circadian Regulation ◽  
The Core ◽  
Steroidogenic Cells ◽  
First Time ◽  
A172 Glioma Cells

Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles.

scholarly journals Translin-associated Factor X Is Post-transcriptionally Regulated by Its Partner Protein TB-RBP, and Both Are Essential for Normal Cell Proliferation

2004 ◽  
Vol 279 (13) ◽  
pp. 12605-12614 ◽  
Author(s):  
Shicheng Yang ◽  
Yoon Shin Cho ◽  
Vargheese M. Chennathukuzhi ◽  
Lara A. Underkoffler ◽  
Kathleen Loomes ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Normal Cell ◽  
Factor X ◽  
Associated Factor ◽  
Partner Protein

Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X

2014 ◽  
Vol 135 (9) ◽  
pp. 2054-2064 ◽  
Author(s):  
Nan Qin ◽  
Aguirre A. de Cubas ◽  
Ruben Garcia-Martin ◽  
Susan Richter ◽  
Mirko Peitzsch ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Chromaffin Cell ◽  
Factor X ◽  
Tumor Cell Proliferation ◽  
Associated Factor ◽  
Phenotypic Features ◽  
Opposing Effects

scholarly journals Phosphatidylinositol 5 Phosphate (PI5P): From Behind the Scenes to the Front (Nuclear) Stage

2019 ◽  
Vol 20 (9) ◽  
pp. 2080 ◽  
Author(s):  
Alessandro Poli ◽  
Antonio Enrico Zaurito ◽  
Shidqiyyah Abdul-Hamid ◽  
Roberta Fiume ◽  
Irene Faenza ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Chromatin Remodeling ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Cycles ◽  
The Core ◽  
Nuclear Stage ◽  
Cellular Compartments

Phosphatidylinositol (PI)-related signaling plays a pivotal role in many cellular aspects, including survival, cell proliferation, differentiation, DNA damage, and trafficking. PI is the core of a network of proteins represented by kinases, phosphatases, and lipases which are able to add, remove or hydrolyze PI, leading to different phosphoinositide products. Among the seven known phosphoinositides, phosphatidylinositol 5 phosphate (PI5P) was the last to be discovered. PI5P presence in cells is very low compared to other PIs. However, much evidence collected throughout the years has described the role of this mono-phosphoinositide in cell cycles, stress response, T-cell activation, and chromatin remodeling. Interestingly, PI5P has been found in different cellular compartments, including the nucleus. Here, we will review the nuclear role of PI5P, describing how it is synthesized and regulated, and how changes in the levels of this rare phosphoinositide can lead to different nuclear outputs.

scholarly journals Cardiolipin Synthesis in Skeletal Muscle Is Rhythmic and Modifiable by Age and Diet

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Kazunari Nohara ◽  
Eunju Kim ◽  
Marvin Wirianto ◽  
Eugenia Mileykovskaya ◽  
William Dowhan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Healthy Aging ◽  
C2c12 Cells ◽  
C2c12 Myotubes ◽  
Circadian Regulation ◽  
Aged Mice ◽  
Rhythmic Expression ◽  
Genes Encoding

Circadian clocks regulate metabolic processes in a tissue-specific manner, which deteriorates during aging. Skeletal muscle is the largest metabolic organ in our body, and our previous studies highlight a key role of circadian regulation of skeletal muscle mitochondria in healthy aging. However, a possible circadian regulation of cardiolipin (CL), the signature lipid class in the mitochondrial inner membrane, remains largely unclear. Here, we show that CL levels oscillate during the diurnal cycle in C2C12 myotubes. Disruption of the Ror genes, encoding the ROR nuclear receptors in the secondary loop of the circadian oscillator, in C2C12 cells was found to dampen core circadian gene expression. Importantly, several genes involved in CL synthesis, including Taz and Ptpmt1, displayed rhythmic expression which was disrupted or diminished in Ror-deficient C2C12 cells. In vivo studies using skeletal muscle tissues collected from young and aged mice showed diverse effects of the clock and aging on the oscillatory expression of CL genes, and CL levels in skeletal muscle were enhanced in aged mice relative to young mice. Finally, consistent with a regulatory role of RORs, Nobiletin, a natural agonist of RORs, was found to partially restore transcripts levels of CL synthesis genes in aged muscle under a dietary challenge condition. Together, these observations highlight a rhythmic CL synthesis in skeletal muscle that is dependent on RORs and modifiable by age and diet.

Plasma Levels of Protein S, Protein C, and Factor X: Effects of Sex, Hormonal State and Age

1995 ◽  
Vol 74 (05) ◽  
pp. 1271-1275 ◽  
Author(s):  
C M A Henkens ◽  
V J J Bom ◽  
W van der Schaaf ◽  
P M Pelsma ◽  
C Th Smit Sibinga ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Postmenopausal Women ◽  
Protein C ◽  
Blood Donors ◽  
Premenopausal Women ◽  
Protein S ◽  
The Other ◽  
Factor X ◽  
Normal Ranges

SummaryWe measured total and free protein S (PS), protein C (PC) and factor X (FX) in 393 healthy blood donors to assess differences in relation to sex, hormonal state and age. All measured proteins were lower in women as compared to men, as were levels in premenopausal women as compared to postmenopausal women. Multiple regression analysis showed that both age and subgroup (men, pre- and postmenopausal women) were of significance for the levels of total and free PS and PC, the subgroup effect being caused by the differences between the premenopausal women and the other groups. This indicates a role of sex-hormones, most likely estrogens, in the regulation of levels of pro- and anticoagulant factors under physiologic conditions. These differences should be taken into account in daily clinical practice and may necessitate different normal ranges for men, pre- and postmenopausal women.

The Activation of Human Factor X in Sodium Citrate: the Role of Factor VII

1976 ◽  
Vol 36 (01) ◽  
pp. 104-114 ◽  
Author(s):  
D. L Aronson ◽  
A. J Mustafa
Keyword(s):  
Sodium Citrate ◽  
Human Factor ◽  
Deae Cellulose ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X

SummaryHuman factor X was purified by several different procedures yielding products which had varying amounts of factor VII and factor IX. Treatment with CHC13 during the fractionation of the factor X removed 95% of the factor VII and factor IX activity and the resulting factor X activated more slowly when incubated in 25% sodium citrate. Removal of residual factor VII by DEAE cellulose chromatography yielded a factor X which activated still more slowly and less completely. When the factor VII, removed by chromatography, was added to the chromatographed factor X, the ability to be activated in 25% sodium citrate was restored. Confirmatory evidence for the role of factor VII in this reaction was the inhibition of the conversion of the factor X by both DFP and SBTI.

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