The MDM2 oncogene has both p53-dependent and p53-independent activities. We have previously reported that antisense MDM2 inhibitors have significant antitumor activity in multiple human cancer models with various p53 statuses (Zhang, Z., Li, M., Wang, H., Agrawal, S., and Zhang, R. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 11636 -11641). We have also provided evidence that MDM2 has a direct role in the regulation of p21, a cyclin-dependent kinase inhibitor. Here we provide evidence supporting functional interaction between MDM2 and p21 in vitro and in vivo. The inhibition of MDM2 with anti-MDM2 antisense oligonucleotide or Short Interference RNA targeting MDM2 significantly elevated p21 protein levels in PC3 cells (p53 null). In contrast, overexpression of MDM2 diminished the p21 level in the same cells by shortening the p21 half-life, an effect reversed by MDM2 antisense inhibition. MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180 -298 of the MDM2 protein. In summary, we provide evidence supporting a physical interaction between MDM2 and p21. We also demonstrate that, by reducing p21 protein stability via proteasome-mediated degradation, MDM2 functions as a negative regulator of p21, an effect independent of both p53 and ubiquitination. p21WAF1/CIP1 , which belongs to the CIP/KIP1 family of cyclindependent kinase inhibitors, has long been characterized as an inhibitor of cell proliferation, but increasing evidence suggests that it plays a role in cell differentiation, senescence, and modulation of apoptosis (1). The regulation of p21 also may be more complicated than previously thought (3-5). Its transcription can be regulated through p53-dependent (2) and -independent pathways (3); its degradation is also processed by ubiquitin-dependent (4) and -independent (5) pathways via proteasome-mediated mechanisms.The MDM2 1 (mouse double minute 2) oncoprotein is a negative regulator of p53 (6) that functions through blocking its transcriptional activity (7) and promoting its proteasome-mediated degradation (8). However, MDM2 now has been shown to interact with other cellular proteins including p19/14 ARF (9), E2F1 (10), p300 (11), ribosomal L5 protein (12), and p73 (13), suggesting that it has p53-independent activities (6). The Ring finger domain in the C terminus of MDM2, containing the ubiquitin E3 ligase activity, is responsible for p53 ubiquitination and subsequent degradation (14). More recently, this E3 ligase has also been shown to facilitate the proteasome-dependent degradation of the androgen receptor (15).The MDM2 oncoprotein is overexpressed in many human malignancies, and high MDM2 levels are associated with a poor prognosis (6). The MDM2 oncoprotein may also have a role in cancer therapy. We have recently developed specifi...

Spin-orbit coupling (SOC), the interaction between the spin and momentum of a quantum particle, is crucial for many important condensed matter phenomena. The recent experimental realization of SOC in neutral bosonic cold atoms provides a new and ideal platform for investigating spin-orbit coupled quantum many-body physics. In this Letter, we derive a generic Gross-Pitaevskii equation as the starting point for the study of many-body dynamics in spin-orbit coupled Bose-Einstein condensates. We show that different laser setups for realizing the same SOC may lead to different mean-field dynamics. Various ground state phases (stripe, phase separation, etc.) of the condensate are found in different parameter regions. A new oscillation period induced by the SOC, similar to the Zitterbewegung oscillation, is found in the center-of-mass motion of the condensate.

The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53 null ), curcumin reduced MDM2 protein and mRNA in a dose-and time-dependent manner, and enhanced the expression of the tumor suppressor p21 Waf1/CIP1 . The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 overexpression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent. [Cancer Res 2007;67(5):1988-96]

Majorana fermions (MFs), quantum particles that are their own antiparticles, are not only of fundamental importance in elementary particle physics and dark matter, but also building blocks for fault-tolerant quantum computation. Recently MFs have been intensively studied in solid state and cold atomic systems. These studies are generally based on superconducting pairing with zero total momentum. On the other hand, finite total momentum Cooper pairings, known as Fulde-Ferrell (FF) Larkin-Ovchinnikov (LO) states, were widely studied in many branches of physics. However, whether FF and LO superconductors can support MFs has not been explored. Here we show that MFs can exist in certain types of gapped FF states, yielding a new quantum matter: topological FF superfluids/superconductors. We demonstrate the existence of such topological FF superfluids and the associated MFs using spin-orbitcoupled degenerate Fermi gases and derive their parameter regions. The implementation of topological FF superconductors in semiconductor/superconductor heterostructures is also discussed.

Background and Aims There is growing evidence that single‐stranded, circular RNA (circRNA) plays a key role in the development of certain cancers, including hepatocellular carcinoma (HCC). It is less clear, however, what role circRNA plays in HCC metastasis. Approach and Results In this study, through circRNA sequencing, we identified a circRNA: circASAP1 (a circRNA derived from exons 2 and 3 of the ASAP1 gene, hsa_circ_0085616), which is associated with pulmonary metastasis after curative resection in patients with HCC. CircASAP1 was overexpressed in HCC cell lines with high metastatic potential and in metastatic HCCs. In vitro, circASAP1 promoted cell proliferation, colony formation, migration, and invasion, and in vivo, it enhanced tumor growth and pulmonary metastasis. Mechanism studies showed that circASAP1 acts as a competing endogenous RNA for microRNA 326 (miR‐326) and microRNA 532‐5p (miR‐532‐5p), both of which are tumor suppressors in HCC. We found that mitogen‐activated protein kinase (MAPK) 1 and colony stimulating factor (CSF)‐1 were direct common targets for microRNA 326 (miR‐326) and microRNA 532‐5p (miR‐532‐5p), which were regulated by circASAP1. CircASAP1 promotes HCC cell proliferation and invasion by regulating miR‐326/miR‐532‐5p‐MAPK1 signaling and, furthermore, mediates tumor‐associated macrophage infiltration by regulating the miR‐326/miR‐532‐5p‐CSF‐1 pathway. Clinical HCC samples exhibited a positive correlation between circASAP1 expression and levels of CSF‐1, MAPK1, and CD68+ tumor‐associated macrophages, all of which were predictive of patient outcomes. Conclusion We identified circASAP1 as a key regulator of HCC metastasis that acts on miR‐326/miR‐532‐5p‐MAPK1/CSF‐1 signaling and serves as a prognostic predictor in patients with HCC.

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Second order optical nonlinear processes involve the coherent mixing of two electromagnetic waves to generate a new optical frequency, which plays a central role in a variety of applications, such as ultrafast laser systems, rectifiers, modulators, and optical imaging. However, progress is limited in the mid-infrared (MIR) region due to the lack of suitable nonlinear materials. It is desirable to develop a robust system with a strong, electrically tunable second order optical nonlinearity. Here, we demonstrate theoretically that AB-stacked bilayer graphene (BLG) can exhibit a giant and tunable second order nonlinear susceptibility χ((2)) once an in-plane electric field is applied. χ((2)) can be electrically tuned from 0 to ~10(5) pm/V, 3 orders of magnitude larger than the widely used nonlinear crystal AgGaSe(2). We show that the unusually large χ((2)) arise from two different quantum enhanced two-photon processes thanks to the unique electronic spectrum of BLG. The tunable electronic bandgap of BLG adds additional tunability on the resonance of χ((2)), which corresponds to a tunable wavelength ranging from ~2.6 to ~3.1 μm for the up-converted photon. Combined with the high electron mobility and optical transparency of the atomically thin BLG, our scheme suggests a new regime of nonlinear photonics based on BLG.