In contrast to most genomic DNA in mitotic cells, the promoter regions of some genes, such as the stress-inducible hsp70i gene that codes for a heat shock protein, remain uncompacted, a phenomenon called bookmarking. Here we show that hsp70i bookmarking is mediated by a transcription factor called HSF2, which binds this promoter in mitotic cells, recruits protein phosphatase 2A, and interacts with the CAP-G subunit of the condensin enzyme to promote efficient dephosphorylation and inactivation of condensin complexes in the vicinity, thereby preventing compaction at this site. Blocking HSF2-mediated bookmarking by HSF2 RNA interference decreases hsp70i induction and survival of stressed cells in the G1 phase, which demonstrates the biological importance of gene bookmarking.
Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P Ͻ 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P Ͻ 0.05 and P Ͻ 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P Ͻ 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring.running; pregnancy; programming; mice IN 2007, 23.5 MILLION PEOPLE in the US were estimated to have diabetes, and this number is increasing (4). Interestingly, and what is often underappreciated, is that the metabolic status of an individual is decided not only by their inherited genes, nutritional intake, and physical exercise but also by maternal nutrition and obesity during pregnancy. In 1992, Hales and Barker (18) put forth the thrifty phenotype hypothesis that suggested that malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity, diabetes, and heart disease in adulthood. This hypothesis has since been modified to the developmental origins of health and disease (DOHaD) (15,17,18).The DOHaD suggests that the maternal environment and fetal programming lead to a higher incidence of several diseases later in life (14, 16). A growing number of studies have been designed to provide evidence for the negative impact of DOHaD, using mice, rats, and sheep as animal models (11,12,31,38). Many of these studies are directed at malnutrition through protein restriction or physical stressors that produce similar effects (8,11,34,44,45), but more recent studies are elucidating the metabolic effects of high-fat diet consumption during pregnancy on offspring (22,38,44,48).It has been known since Hippocrates and Galen that physical activity is an important component of a healthy lifestyle (33). However, knowledge about the contributions of maternal exercise during pregnancy and the long-term consequences on offspring is minimal. In both rats and mice, maternal exercise during pregnancy can improve brain physiology and cognition...
Hyperglycemia in diabetes mellitus promotes oxidative stress in endothelial cells, which contributes to development of cardiovascular diseases. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor activated by oxidative stress that regulates expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes. This study was designed to elucidate the homeostatic role of adaptive induction of Nrf2-driven free radical detoxification mechanisms in endothelial protection under diabetic conditions. Using a Nrf2/antioxidant response element (ARE)-driven luciferase reporter gene assay we found that in a cultured coronary arterial endothelial cell model hyperglycemia (10-30 mmol/l glucose) significantly increases transcriptional activity of Nrf2 and upregulates the expression of the Nrf2 target genes NQO1, GCLC, and HMOX1. These effects of high glucose were significantly attenuated by small interfering RNA (siRNA) downregulation of Nrf2 or overexpression of Keap-1, which inactivates Nrf2. High-glucose-induced upregulation of NQO1, GCLC, and HMOX1 was also prevented by pretreatment with polyethylene glycol (PEG)-catalase or N-acetylcysteine, whereas administration of H(2)O(2) mimicked the effect of high glucose. To test the effects of metabolic stress in vivo, Nrf2(+/+) and Nrf2(-/-) mice were fed a high-fat diet (HFD). HFD elicited significant increases in mRNA expression of Gclc and Hmox1 in aortas of Nrf2(+/+) mice, but not Nrf2(-/-) mice, compared with respective standard diet-fed control mice. Additionally, HFD-induced increases in vascular ROS levels were significantly greater in Nrf2(-/-) than Nrf2(+/+) mice. HFD-induced endothelial dysfunction was more severe in Nrf2(-/-) mice, as shown by the significantly diminished acetylcholine-induced relaxation of aorta of these animals compared with HFD-fed Nrf2(+/+) mice. Our results suggest that adaptive activation of the Nrf2/ARE pathway confers endothelial protection under diabetic conditions.
Small ubiquitin-like modifier (SUMO) 1 is a protein of 97 amino acids that is structurally similar to ubiquitin and has been called by other names including Smt3p, Pmt2p, PIC-1, GMP1, Ubl1, and Sentrin (1). Like ubiquitin, SUMO has been found to be covalently attached to certain lysine residues of specific target proteins (2). In contrast to ubiquitination, however, sumoylation does not promote the degradation of proteins but instead alters a number of different functional parameters of proteins, depending on the protein substrate in question. These parameters include but are not limited to properties such as subcellular localization, protein partnering, and DNA-binding and/or transactivation functions of transcription factors (2-4). The contrast between the functional effects of ubiquitination and sumoylation is most striking in the case of IB, where sumoylation stabilizes the protein by modifying the same residue that is ubiquitinated, thereby directly competing with that pathway (5). This review will focus on the regulation of SUMO modification and its role in controlling the functional properties of proteins. The reader is also referred to other excellent reviews on this topic (2-4, 6 -8). Enzymology and Regulation of SUMO Conjugationand Deconjugation Three different ubiquitous SUMO-related proteins have been identified in mammalian cells, SUMO-1, SUMO-2, and SUMO-3, with SUMO-2 and SUMO-3 having greater sequence relatedness with each other than with 4). Recently a tissue-specific SUMO-4 has been identified in human kidney with homology to SUMO-2/3, which raises the possibility that some SUMO proteins could have tissue-dependent functions (9). SUMO modification occurs on the lysine in the consensus sequence ⌿KXE (where ⌿ represents a hydrophobic amino acid, and X represents any amino acid) (2, 3). The mechanism involved in maturation and transfer of SUMO to target substrates is very similar to that seen with ubiquitination and other ubiquitin-like proteins (3, 4). This process involves four enzymatic steps: maturation, activation, conjugation, and ligation ( Fig. 1). In the first step the SUMO protein is cleaved by SUMO-specific carboxyl-terminal hydrolase to produce a carboxyl-terminal diglycine motif. This process of maturation is identical with all three mammalian SUMO forms. After maturation, SUMO proteins are able to be utilized for conjugation to proteins. The SUMO-activating (E1) enzyme is a heterodimer consisting of Aos1 and Uba2 (also known as SAE1/SAE2 or Sua1/hUba2 in humans). Activation of SUMO by the E1 is an ATP-dependent process and results in the formation of a thioester bond between SUMO and the Uba2 subunit of the E1-activating enzyme. Activation is followed by transfer of SUMO from the E1 enzyme to a conserved cysteine in the conjugating (E2) enzyme, Ubc9. This single E2 enzyme identified so far for the sumoylation pathway contrasts with the multiple E2 enzymes involved in attaching ubiquitin to proteins (4, 10).The final step of sumoylation involves ligation of SUMO to the target protei...
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