Sovannarith Korm

ABSTRACTAcross diverse taxa, offspring from older mothers have decreased lifespan and fitness. Little is known about whether such maternal age effects vary among genotypes for a given species, however. We compared maternal age effects among four strains of rotifers in theBrachionus plicatilisspecies complex. For each strain, we measured lifespan, reproductive schedule, and lifetime reproductive output of offspring produced by young, middle-aged, and old mothers. We found unexpected variability among strains in the magnitude and direction of maternal age effects on offspring life history traits. In one strain, offspring of young mothers lived 20% longer than offspring of old mothers, whereas there were no significant effects of maternal age on lifespan for the other strains. Across strains, advanced maternal age had positive effects, negative effects, or no effect on lifetime reproductive output. For all but one strain, older mothers produced offspring that had higher maximum daily r...

The acetylation of p53 is critical in modulating its pro-apoptotic roles. However, its regulatory mechanism and physiological significance are unclear. Here, we show HDAC6 negatively regulates pro-apoptotic acetylation of p53 at lysine residue 120 (K120) in mesenchymal stem cells (MSCs). The loss of HDAC6 expression in MSCs increases K120 acetylation of p53, which is successfully reversed by the wild-type but not by catalytically dead HDAC6. Deletion of HDAC6 induces caspase-dependent apoptosis by promoting transactivation of Bax and suppression of Bcl-2. Moreover, HDAC6 deficiency leads to mitochondrial dysfunction characterized by aberrant reactive oxygen species production and defective oxidative phosphorylation, which is reversed by ectopic expression of wild-type or acetylation mimetic p53. This study demonstrates that HDAC6 is a critical regulator of a pro-apoptotic p53 K120 acetylation and mitochondrial function in MSCs, suggesting that the modulation of HDAC6 activity could ...

Epithelial-mesenchymal transition (EMT) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the down-regulation of RAP80, a well-known regulator for DNA damage response. The knockdown of RAP80 leads to EMT-like morphological changes and the increase of tumor sphere formation in non-adhesive culture. Mechanistically, RAP80 controls a reciprocal regulatory axis of ZEB1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP80 increases ZEB1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E-cadherin, p16, and p21 expression. Using in vivo metastasis analysis, RAP80 knockdown cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to control. Interestingly, the expre...

Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize rec...

Keywords: Histone deacetylase 6 (HDAC6) Uncoupling protein 1 (UCP1) Mitochondrial thermogenesis Brown adipose tissue (BAT) cAMP PKA a b s t r a c t Mitochondrial uncoupling protein 1 (UCP1) is responsible for nonshivering thermogenesis in brown adipose tissue (BAT). UCP1 increases the conductance of the inner mitochondrial membrane (IMM) for protons to make BAT mitochondria generate heat rather than ATP. HDAC6 is a cytosolic deacetylase for non-histone substrates to regulate various cellular processes, including mitochondrial quality control and dynamics. Here, we showed that the body temperature of HDAC6 knockout mice is slightly decreased in normal hosing condition. Interestingly, UCP1 was downregulated in BAT of HDAC6 knockout mice, which extensively linked mitochondrial thermogenesis. Mechanistically, we showed that cAMP-PKA signaling plays a key role in HDAC6-dependent UCP1 expression. Notably, the size of brown adipocytes and lipid droplets in HDAC6 knockout BAT is increased. Taken together, our findings suggested that HDAC6 contributes to mitochondrial thermogenesis in BAT by increasing UCP1 expression through cAMP-PKA signaling pathway.

RAP80, a member of the BRCA1-A complex, is a well-known crucial regulator of cell cycle checkpoint and DNA damage repair in the nucleus. However, it is still unclear whether Rap80 localizes to another region outside the nucleus and plays different roles with its partners. Here, we found mitochondrial p32 as a novel binding partner of RAP80 by using yeast two-hybrid screening. RAP80 directly binds the internal region of p32 through its arginine rich C-terminal domain. Based on the interaction, we showed that a subset of RAP80 localizes to mitochondria where p32 exists. Loss of function study revealed that RAP80 deficiency reduces the protein level of p32 and p32 dependent mitochondrial translating proteins such as Rieske and COX1. As a result, mitochondrial membrane potential and oxygen consumption are reduced in RAP80 knockdown cells, indicating mitochondrial dysfunction. Our study identifies a novel interaction between RAP80 and p32, which is important for preserving intact mitochondrial function.

Epithelial–mesenchymal transition (EMT) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the downregulation of RAP80, a well-known regulator for DNA damage response. The knockdown of RAP80 leads to EMT-like morphological changes and the increase of tumor sphere formation in non-adhesive culture. Mechanistically, RAP80 controls a reciprocal regulatory axis of ZEB1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP80 increases ZEB1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E-cad-herin, p16 and p21 expression. Using in vivo metastasis analysis, RAP80 knock-down cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to controls. Interestingly, the expression level of RAP80 was positively correlated with the survival rate in lung adenocarci-noma and breast cancer patients. These findings indicate that RAP80 is a critical gatekeeper in impeding EMT-induced metastasis and malignant phenotypes of cancer as well as preserving DNA integrity. D NA damage response (DDR) is essential to genomic integrity by preventing the accumulation and transmission of mutations. (1) DDR is frequently found in precancerous lesions and believed to be a barrier to tumorigenesis by induction of senescence or death in cells with excessive DNA damage. (2,3) Although the tumor-suppressive roles of DDR in early premalignant lesions are well established, (4,5) the function of DDR is unclear in tumor progression during later stages, such as metastasis and tumor malignancy. Receptor-associated protein 80 (RAP80 or UIMC1) is an ubiquitin interaction motif-containing (UIMC) nuclear protein that facilitates the recruitment of the BRCA1-BARD1-Abraxas ⁄ CCDC98-MERIT-BRCC36 complex to DNA damage sites, which initiates DDR. (6–13) Although previous studies indicate that defective RAP80 function ⁄ expression could lead to geno-mic instability and subsequent increased early stage cancer risk, (14–16) the possible role of RAP80 on tumor progression and malignancy in later stages, including EMT-derived metastasis, has not been investigated. Recently, the convergence of DDR and epithelial– mesenchymal transition (EMT) in cancer development was reported. (17,18) EMT trans-differentiation can generate cells with stem-like properties. (18) Cancer stem cells have been known to be resistant against DNA damage through activation of DDR. (19,20) Notably, the EMT regulator ZEB1 also promotes DDR and tumor resistance to DNA damage, suggesting that ZEB1 could be a convergent regulator for both EMT and DDR. (17) In this study, we investigate the effect of the downregulation of RAP80 expression on EMT and cancer metastasis. We show

Information on the level of contamination due to bacterial and fungal infestation on some of the freshly supplied fruit and vegetables in Camodia is still limited, but this issue has become interesting in through some NGOs and institute, for example. The study determined the microbial load of some freshly supplied fruit and vegetables in Cambodia which included Cucumber, Salad, Mango, and Banana by comparing between harvest and post-harvest. The fruit and vegetable samples was isolated bacteria and fungi by using Nutrient broth-yeast extract agar media (for bacteria) and Potato dextrose agar with ampicillin and streptromicin (for fungi). The fungi were incubated for two day and the bacteria for three days at 280C. The result of microbial test showed that average bacteria load on Cucumber, Salad, Mango and Banana during harvest had 366.67×104CFU/g, 1127.33×104CFU/g, 590.00×104CFU/g and 98.33×104CFU/g respectively, and during post-harvest had 610.00×104CFU/g, 41.67×104CFU/g, 6.30×104CFU/g and 0.16×104CFU/g respectively. During harvest average fungi load on Cucumber, Salad, Mango and Banana had 1.67×104CFU/g, 2.67×104CFU/g, 2.67×104CFU/g and 1.33×104CFU/g respectively and average fungi load during post-harvest had 45.00×104CFU/g, 4.20×104CFU/g, 0.54×104CFU/g and 0.06×104CFU/g respectively. The Unpaired t-test result in SPSS showed fungi load on Cucumber highly increasing statistic significant (P<0.05) between during harvest and post-harvest, and the rest are not statistic significant (P>0.05).