Sujin Park

Smad7 enhances ATM activity by facilitating the interaction between ATM and Mre11-Rad50-Nbs1 complex in DNA double-strand break repair

Genomic instability is one of the representative causes in genetic disorder, where the proper cellular response to DNA damage is essential in maintaining genomic stability. ATM and the Mre11-Rad50-Nbs1 (MRN) complex play critical roles in the cellular response to DNA damage such as DNA double-strand break (DSB). In this study, we report that Smad7 is indispensible in DNA damage response as a novel component of MRN complex. Smad7 enhances cell survival against DNA damage by accelerating ATM dependent DNA repair signaling. In Smad7-deficient mouse embryonic fibroblast cells, the loss of Smad7 decreases ATM activation and inhibits recruitment of ATM to the sites of DSBs. Smad7 interacts with Nbs1, a member of MRN complex, and enhances the interaction between ATM and Nbs1 upon DNA damage response, leading to phosphorylation of downstream substrates. Ectopic expression of Smad7 in the skin of mice enhances the phosphorylation of ATM upon X-irradiation. We found that effect of Smad7 on enhancing DNA repair is independent of its inhibitory activity of TGF-β signaling. Taken together, our results highlight a critical function of Smad7 in DSB response and establish the novel mechanism in which Smad7 facilitates the recruitment of ATM to the MRN complex through direct interaction with Nbs1.

Myristica fragrans Seed Extract Protects Against Dextran Sulfate Sodium–Induced Colitis in Mice

Nutmeg (seed of Myristica fragrans [MF]) is one of the most commonly used spices in the world and also a well-known herb for the treatment of various intestinal diseases, including colitis in traditional Korean medicine. The purpose of the current study was to investigate whether water extract of MF (MFE) can protect against dextran sulfate sodium (DSS) induced colitis in a mouse model. Colitis was induced by 5% DSS in balb/c mice. MFE (100, 300 or 1000 mg/kg) was orally administered to the mice twice a day for 7 days. Body weight, colon length, clinical score, and histological score were assessed to determine the effects on colitis. Proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6) were measured to investigate the mechanisms of action. MFE dose dependently inhibited the colon shortening and histological damage to the colon. However, it did not prevent weight loss. MFE also inhibited proinflammatory cytokines. The current results suggest that MFE ameliorates DSS-induced colitis in mice by inhibiting inflammatory cytokines. Further investigation, including the exact mechanisms is needed.

AnyHeart: A single-piece heart-saving implantable artificial heart (BVAD): Monitoring and estimation

AnyHeart is a single-piece, implantable biventricular assist device. This electromechanical BVAD has a moving-actuator mechanism. To monitor the status of AnyHeart from anywhere at any time, a portable personal digital assistant (PDA) monitor and web-based remote monitoring system were developed. The PDA local monitoring system has replaced bulky personal computer monitoring systems. The web-based remote monitoring system has several functions such as data collecting, storing, and posting through the internet. Basically, interventricular pressure (IVP) is a parameter indicating the filling level of the blood chambers of AnyHeart. The pump output can be estimated using IVP, which is acquired noninvasively from AnyHeart. With the proposed method, we can estimate the pump output with a small margin of error.

Galangin enhances TGF-β1-mediated growth inhibition by suppressing phosphorylation of threonine 179 residue in Smad3 linker region

Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells. However, the mechanism of action of galangin in various cancers remains unclear, and there has been no report concerning regulation of Smad3 phosphorylation by galangin. In the present study, we show that galangin significantly induced apoptosis and inhibited cell proliferation in the presence of TGF-β1 in both human prostate and pancreatic cancer cell lines. Particularly, galangin effectively inhibits phosphorylation of the Thr-179 site at Smad3 linker region through suppression of CDK4 phosphorylation. Thus, galangin can be a promising candidate as a selective inhibitor to suppress phosphorylation of Smad3 linker region.

Relationship Between Atrial Pressures and the Interventricular Pressure in the Moving Actuator Type Total Artificial Heart

The right and left atrial pressures are important parameters in the automatic control of a total artificial heart (TAH) within normal physiological ranges. Our TAH is composed of a moving actuator, right and left ventricles, and the interventricular space (IVS) enclosed by a semirigid housing. During operation of the TAH, the IVS volume is changed dynamically by the difference between the ejection volume of one ventricle and the inflow volume of the other. Therefore, the change in pressure of the IVS is related to both right and left atrial pressures. We measured the interventricular pressure (IVP) waveform using a pressure sensor and attempted to estimate indirectly the changes in atrial pressures. This method has the advantage that the sensor does not contact the blood directly. Furthermore, the IVP waveform has a zero baseline in each pump cycle, thus the pressure measurements are free from transducer drift problems because the peak pressure can be measured from these baseline values. From in vitro experiments, we found that the IVP waveform contained several useful parameters such as negative peak IVP value, dP/dton the initial break, and the area enclosed by the profile for each stroke, each of which are associated with the left and right atrial pressures and the filling conditions of the ventricles. The measured atrial pressures were linearly related to the negative peak value of the interventricular pressure.

Abstract 1774: Emerging role of Smad7 in DNA damage response pathway as a positive regulator.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The cellular response to DNA damage is essential in maintaining genomic stability. As DNA damage accumulates, the occurrence rate of cancer is significantly enhanced. Smad7 is known as an inhibitory Smad which negatively regulates TGF-β-induced signaling pathway. Smad7 is predominantly localized in the nucleus even without TGF-β stimulation. However, TGF-β-independent Smad7 function in the nucleus is still not clear. Here, we report Smad7 regulates DNA damage signaling in response to double-strand break induced by radiomimetic drug, neocarzinostatin (NCS). Smad7 overexpression accelerates DNA repair by enhancing phosphorylation of ATM and γH2AX, major DNA damage response signaling, after DNA damage. In Smad7−/− MEF cell, loss of Smad7 leads to failure of ATM phosphorylation and nuclear foci formation at the site of DNA damage upon NCS treatment. We show that Smad7 interacts with activated ATM/MRN complex and this interaction is significantly increased after DNA damage. Additionally, Smad7 co-localizes with pATM, MRN complex and γH2AX at the sites of DNA damage. Taken together, our data suggests that Smad7 plays a critical role in DNA damage response pathway through interaction with activated ATM. In this study, we reveal the de novo function of Smad7 in the nucleus. Citation Format: Sujin Park, Jin Muk Kang, Staci Jakyong Kim, Hyojung Kim, Seong-Jin Kim. Emerging role of Smad7 in DNA damage response pathway as a positive regulator. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2013-1774

Differential Tissue-specific and Pathway-specific Anti-obesity Effects of Green Tea and Taeumjowitang, a Traditional Korean Medicine, in Mice

Background Traditional medicines have been leveraged for the treatment and prevention of obesity, one of the fastest growing diseases in the world. However, the exact mechanisms underlying the effects of traditional medicine on obesity are not yet fully understood. Methods We produced the transcriptomes of epididymal white adipose tissue (eWAT), liver, muscle, and hypothalamus harvested from mice fed a normal diet, high-fat-diet alone, high-fat-diet together with green tea, or a high-fat-diet together with Taeumjowitang, a traditional Korean medicine. Results We found tissue-specific gene expression patterns as follows: (i) the eWAT transcriptome was more significantly altered by Taeumjowitang than by green tea, (ii) the liver transcriptome was similarly altered by Taeumjowitang and green tea, and (iii) both the muscle and hypothalamus transcriptomes were more significantly altered by green tea than Taeumjowitang. We then applied integrated network analyses, which revealed that functional networks associated with lymphocyte activation were more effectively regulated by Taeumjowitang than by green tea in the eWAT. In contrast, green tea was a more effective regulator of functional networks associated with glucose metabolic processes in the eWAT. Conclusions Taeumjowitang and green tea have a differential tissue-specific and pathway-specific therapeutic effect on obesity.

Abstract 25: CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-beta signaling

CBL protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL highly expresses in breast cancer cells and significantly inhibits TGF-β tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, SERPINE1 and CDK inhibitors such as p15 INK4b and p21 Cip1 . Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues and the loss of CBL decreases a tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 25. doi:1538-7445.AM2012-25

Acoustical Characteristics of a Moving Actuator Type Total Artificial Heart

The study attempts to characterize the acoustic emission from a moving actuator type, totally implantable, electromechanical, artificial heart. In vitro measurements were made on the acoustic emission from the artificial heart using a highly sensitive measuring microphone, under various operating conditions. Time-frequency spectral analysis, based on the reduced interference distribution kernel, was employed to identify the effects of control parameters of the artificial heart on the acoustic emission. The control parameters considered in this study were the electric current supplied to the d.c. motor of the artificial heart, stroke angle, and the initial interventricular space pressure. The measured acoustic signals were seen to be nonstationary even if a beat cycle yields the periodical repetition by the heart rate. It was shown that the primary spectral peak occurred at 370 Hz under normal operating conditions: stroke angle 140°, initial interventricular space pressure 0 mmHg, and current level 15. The current level used here has no unit and is not directly related to the actual current but controls the motor speed. The primary peak frequency linearly increased with the current level, but was insensitive to the initial interventricular space pressure. When the current level was high, several secondary peaks appeared above 1100 Hz which did not exist at low current levels. The time-frequency energy distribution revealed that the primary frequency, representing the rotational velocity of the motor, was apparent around the middle of both systolic and diastolic periods, and reached its maximum. In contrast, the secondary high-pitched sounds appeared as the cycle approached the end of the systolic period of the left ventricle. It seems that these high-frequency spectral peaks resulted from sac folding and gear sliding. The influence of the motor current on acoustic spectra becomes more significant if the stroke angle of the actuator is increased.