Mdm2 RING Mutation Enhances p53 Transcriptional Activity and p53-p300 Interaction

The p53 transcription factor and tumor suppressor is regulated primarily by the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 to target it for proteasomal degradation. Aside from its ubiquitin ligase function, Mdm2 has been believed to be capable of suppressing p53's transcriptional activity by binding with and masking the transactivation domain of p53. The ability of Mdm2 to restrain p53 activity by binding alone, without ubiquitination, was challenged by a 2007 study using a knockin mouse harboring a single cysteine-to-alanine point mutation (C462A) in Mdm2's RING domain. Mouse embryonic fibroblasts with this mutation, which abrogates Mdm2's E3 ubiquitin ligase activity without affecting its ability to bind with p53, were unable to suppress p53 activity. In this study, we utilized the Mdm2C462A mouse model to characterize in further detail the role of Mdm2's RING domain in the control of p53. Here, we show in vivo that the Mdm2C462A protein not only fails to suppress p53, but compared to the complete absence of Mdm2, Mdm2C462A actually enhances p53 transcriptional activity toward p53 target genes p21/CDKN1A, MDM2, BAX, NOXA, and 14-3-3σ. In addition, we found that Mdm2C462A facilitates the interaction between p53 and the acetyltransferase CBP/p300, and it fails to heterodimerize with its homolog and sister regulator of p53, Mdmx, suggesting that a fully intact RING domain is required for Mdm2's inhibition of the p300-p53 interaction and for its interaction with Mdmx. These findings help us to better understand the complex regulation of the Mdm2-p53 pathway and have important implications for chemotherapeutic agents targeting Mdm2, as they suggest that inhibition of Mdm2's E3 ubiquitin ligase activity may be sufficient for increasing p53 activity in vivo, without the need to block Mdm2-p53 binding

pRb or its cousins: Who controls the family business?

Comment on: Bazarov A, et al. Cell Cycle 2012; 11:1008–101

X 線、電波観測による銀河団1RXS J0603.3+4214とRXC J1053.7+5453に付随する電波レリック周辺領域での粒子加速過程に関する研究

山形大

Mdm2 RING Mutation Enhances p53 Transcriptional Activity and p53-p300 Interaction

The p53 transcription factor and tumor suppressor is regulated primarily by the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 to target it for proteasomal degradation. Aside from its ubiquitin ligase function, Mdm2 has been believed to be capable of suppressing p53's transcriptional activity by binding with and masking the transactivation domain of p53. The ability of Mdm2 to restrain p53 activity by binding alone, without ubiquitination, was challenged by a 2007 study using a knockin mouse harboring a single cysteine-to-alanine point mutation (C462A) in Mdm2's RING domain. Mouse embryonic fibroblasts with this mutation, which abrogates Mdm2's E3 ubiquitin ligase activity without affecting its ability to bind with p53, were unable to suppress p53 activity. In this study, we utilized the Mdm2C462A mouse model to characterize in further detail the role of Mdm2's RING domain in the control of p53. Here, we show in vivo that the Mdm2C462A protein not only fails to suppress p53, but compared to the complete absence of Mdm2, Mdm2C462A actually enhances p53 transcriptional activity toward p53 target genes p21/CDKN1A, MDM2, BAX, NOXA, and 14-3-3σ. In addition, we found that Mdm2C462A facilitates the interaction between p53 and the acetyltransferase CBP/p300, and it fails to heterodimerize with its homolog and sister regulator of p53, Mdmx, suggesting that a fully intact RING domain is required for Mdm2's inhibition of the p300-p53 interaction and for its interaction with Mdmx. These findings help us to better understand the complex regulation of the Mdm2-p53 pathway and have important implications for chemotherapeutic agents targeting Mdm2, as they suggest that inhibition of Mdm2's E3 ubiquitin ligase activity may be sufficient for increasing p53 activity in vivo, without the need to block Mdm2-p53 binding

Stacks and D-Brane Bundles

In this paper we describe explicitly how the twisted ``bundles'' on a D-brane worldvolume in the presence of a nontrivial B field, can be understood in terms of sheaves on stacks. We also take this opportunity to provide the physics community with a readable introduction to stacks and generalized spaces.Comment: 24 pages, LaTeX; v2: references adde

Suzaku and Chandra observations of the galaxy cluster RXC J1053.7+5453 with a radio relic

We present the results of Suzaku and Chandra observations of the galaxy cluster RXC J1053.7+5453 ($z=0.0704$), which contains a radio relic. The radio relic is located at the distance of $\sim 540$ kpc from the X-ray peak toward the west. We measured the temperature of this cluster for the first time. The resultant temperature in the center is $\sim 1.3$ keV, which is lower than the value expected from the X-ray luminosity - temperature and the velocity dispersion - temperature relation. Though we did not find a significant temperature jump at the outer edge of the relic, our results suggest that the temperature decreases outward across the relic. Assuming the existence of the shock at the relic, its Mach number becomes $M \simeq 1.4$. A possible spatial variation of Mach number along the relic is suggested. Additionally, a sharp surface brightness edge is found at the distance of $\sim 160$ kpc from the X-ray peak toward the west in the Chandra image. We performed X-ray spectral and surface brightness analyses around the edge with Suzaku and Chandra data, respectively. The obtained surface brightness and temperature profiles suggest that this edge is not a shock but likely a cold front. Alternatively, it cannot be ruled out that thermal pressure is really discontinuous across the edge. In this case, if the pressure across the surface brightness edge is in equilibrium, other forms of pressure sources, such as cosmic-rays, are necessary. We searched for the non-thermal inverse Compton component in the relic region. Assuming the photon index $\Gamma = 2.0$, the resultant upper limit of the flux is $1.9 \times 10^{-14} {\rm erg \ s^{-1} \ cm^{-2}}$ for $4.50 \times 10^{-3} {\rm \ deg^{2}}$ area in the 0.3-10 keV band, which implies that the lower limit of magnetic field strength becomes $ 0.7 {\rm \ \mu G}$.Comment: 13page, 8 figures, accepted for publication in PASJ. arXiv admin note: text overlap with arXiv:1508.0584

p32 heterozygosity protects against age- and diet-induced obesity by increasing energy expenditure

Obesity is increasing in prevalence and has become a global public health problem. The main cause of obesity is a perturbation in energy homeostasis, whereby energy intake exceeds energy expenditure. Although mitochondrial dysfunction has been linked to the deregulation of energy homeostasis, the precise mechanism is poorly understood. Here, we identify mitochondrial p32 (also known as C1QBP) as an important regulator of lipid homeostasis that regulates both aerobic and anaerobic energy metabolism. We show that while whole-body deletion of the p32 results in an embryonic lethal phenotype, mice heterozygous for p32 are resistant to age- and high-fat diet-induced ailments, including obesity, hyperglycemia, and hepatosteatosis. Notably, p32 +/- mice are apparently healthy, demonstrate an increased lean-to-fat ratio, and show dramatically improved insulin sensitivity despite prolonged high-fat diet feeding. The p32 +/- mice show increased oxygen consumption and heat production, indicating that they expend more energy. Our analysis revealed that haploinsufficiency for p32 impairs glucose oxidation, which results in a compensatory increase in fatty acid oxidation and glycolysis. These metabolic alterations increase both aerobic and anaerobic energy expenditure. Collectively, our data show that p32 plays a critical role in energy homeostasis and represents a potential novel target for the development of anti-obesity drugs

p53 upregulates PLCε-IP3-Ca2+ pathway and inhibits autophagy through its target gene Rap2B

The tumor suppressor p53 plays a pivotal role in numerous cellular responses as it regulates cell proliferation, metabolism, cellular growth, and autophagy. In order to identify novel p53 target genes, we utilized an unbiased microarray approach and identified Rap2B as a robust candidate, which belongs to the Ras-related GTP-binding protein superfamily and exhibits increased expression in various human cancers. We demonstrated that p53 increases the intracellular IP3 and Ca2+ levels and decreases the LC3 protein levels through its target gene Rap2B, suggesting that p53 can inhibit the autophagic response triggered by starvation via upregulation of the Rap2B-PLCε-IP3-Ca2+ pathway. As a confirmed target gene of p53, we believe that further investigating potential functions of Rap2B in autophagy and tumorigenesis will provide a novel strategy for cancer therapy