ARHI (DIRAS 3), an Imprinted Tumor Suppressor Gene, Binds to Importins, and Blocks Nuclear Translocation of Stat3

ARHI (DIRAS3) is an imprinted tumor suppressor gene whose expression is lost in the majority of breast and ovarian cancers. Unlike its homologs Ras and Rap, ARHI functions as a tumor suppressor. Our previous study showed that ARHI can interact with transcription activator Stat3 and inhibit its nuclear translocation in human breast and ovarian cancer cells. To identify proteins that interact with ARHI in nuclear translocation, we have performed proteomic analysis and identified several importins that can associate with ARHI. To further explore this novel finding, we have purified 10 GST-importin fusion proteins (importin 7, 8, 13, b1, a1, a3, a5, a6, a7 as well as mutant a1). Using a GST-pull down assay, we found that ARHI can bind strongly to most importins; however, its binding is significantly reduced with an importin a1 mutant which contains an altered nuclear localization signal (NLS) domain. In addition, an ARHI N-terminal deletion mutant (NTD) exhibits much less binding to all importins than does wild type ARHI ARHI and NTD proteins were purified and tested for their ability to inhibit nuclear importation of proteins in HeLa cells. ARHI protein inhibits interaction of Ran-importin complexes with GFP fusion proteins that contain an NLS domain and a beta-like import receptor binding domain, blocking their nuclear localization. Addition of ARHI also blocked nuclear localization of phosphorylated Stat3β. By GST-pull down assays, we found that ARHI could compete for Ran-importins binding. Thus, ARHI-induced disruption of importin binding to cargo proteins including Stat3 could serve as an important regulatory mechanism that contributes to the tumor suppressor function of ARHI

The Arches Cluster: Extended Structure and Tidal Radius

At a projected distance of ~26 pc from Sgr A*, the Arches cluster provides insight to star formation in the extreme Galactic Center (GC) environment. Despite its importance, many key properties such as the cluster's internal structure and orbital history are not well known. We present an astrometric and photometric study of the outer region of the Arches cluster (R > 6.25") using HST WFC3IR. Using proper motions we calculate membership probabilities for stars down to F153M = 20 mag (~2.5 M_sun) over a 120" x 120" field of view, an area 144 times larger than previous astrometric studies of the cluster. We construct the radial profile of the Arches to a radius of 75" (~3 pc at 8 kpc), which can be well described by a single power law. From this profile we place a 3-sigma lower limit of 2.8 pc on the observed tidal radius, which is larger than the predicted tidal radius (1 - 2.5 pc). Evidence of mass segregation is observed throughout the cluster and no tidal tail structures are apparent along the orbital path. The absence of breaks in the profile suggests that the Arches has not likely experienced its closest approach to the GC between ~0.2 - 1 Myr ago. If accurate, this constraint indicates that the cluster is on a prograde orbit and is located front of the sky plane that intersects Sgr A*. However, further simulations of clusters in the GC potential are required to interpret the observed profile with more confidence.Comment: 24 pages (17-page main text, 7-page appendix), 24 figures, accepted to Ap

Animal Agriculture in South Carolina

Livestock Production/Industries,

The Quintuplet Cluster: Extended Structure and Tidal Radius

The Quintuplet star cluster is one of only three known young ($<10$ Myr) massive (M $>10^4$ M$_\odot$) clusters within $\sim100$ pc of the Galactic Center. In order to explore star cluster formation and evolution in this extreme environment, we analyze the Quintuplet's dynamical structure. Using the HST WFC3-IR instrument, we take astrometric and photometric observations of the Quintuplet covering a $120''\times120''$ field-of-view, which is $19$ times larger than those of previous proper motion studies of the Quintuplet. We generate a catalog of the Quintuplet region with multi-band, near-infrared photometry, proper motions, and cluster membership probabilities for $10,543$ stars. We present the radial density profile of $715$ candidate Quintuplet cluster members with $M\gtrsim4.7$ M$_\odot$ out to $3.2$ pc from the cluster center. A $3\sigma$ lower limit of $3$ pc is placed on the tidal radius, indicating the lack of a tidal truncation within this radius range. Only weak evidence for mass segregation is found, in contrast to the strong mass segregation found in the Arches cluster, a second and slightly younger massive cluster near the Galactic Center. It is possible that tidal stripping hampers a mass segregation signature, though we find no evidence of spatial asymmetry. Assuming that the Arches and Quintuplet formed with comparable extent, our measurement of the Quintuplet's comparatively large core radius of $0.62^{+0.10}_{-0.10}$ pc provides strong empirical evidence that young massive clusters in the Galactic Center dissolve on a several Myr timescale.Comment: 25 pages (21-page main text, 4-page appendix), 18 figures, submitted to Ap

Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit