Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells

Thyroid hormone,l-thyroxine (T4), has been shown to promote ovarian cancer cell proliferation via a receptor on plasma membrane integrin αvβ3 and to induce the activation of ERK1/2 and expression of programmed death-ligand 1 (PD-L1) in cancer cells. In contrast, resveratrol binds to integrin αvβ3 at a discrete site and induces p53-dependent antiproliferation in malignant neoplastic cells. The mechanism of resveratrol action requires nuclear accumulation of inducible cyclooxygenase (COX)-2 and its complexation with phosphorylated ERK1/2. In this study, we examined the mechanism by which T4impairs resveratrol-induced antiproliferation in human ovarian cancer cells and found that T4inhibited resveratrol-induced nuclear accumulation of COX-2. Furthermore, T4increased expression and cytoplasmic accumulation of PD-L1, which in turn acted to retain inducible COX-2 in the cytoplasm. Knockdown ofPD-L1by small hairpin RNA (shRNA) relieved the inhibitory effect of T4on resveratrol-induced nuclear accumulation of COX-2- and COX-2/p53-dependent gene expression. Thus, T4inhibits COX-2-dependent apoptosis in ovarian cancer cells by retaining inducible COX-2 with PD-L1 in the cytoplasm. These findings provide new insights into the antagonizing effect of T4on resveratrol’s anticancer properties.

Decolonial Queering: The Politics of Being Queer in Palestine

This article analyzes the work of Palestine's most established queer rights organization, alQaws for Sexual and Gender Diversity in Palestinian Society, to reveal the political power of being queer in Palestine. It argues that an open, feminist, queer space such as alQaws is a productive site to think and practice decolonization. Relying on the author's direct involvement with the group, the article traces the development of queer Palestinian thought to provide a critique of queer politics in Palestine: it recounts how since the establishment of the organization in 2001, alQaws activists have increasingly transcended exclusivist gay identifications and rejected singling out sexuality as a discrete site of oppression disconnected from Zionist settler colonialism. The discussion covers Israeli pinkwashing and its counter, Palestinian pinkwatching; it deconstructs pinkwashing narratives, rejects the myth of the colonial savior, and reveals how discourses of sexual progress reproduce Zionist colonialism. It also documents alQaws's challenge to normalizing development discourse.

Duration-Dependent Response of SI to Vibrotactile Stimulation in Squirrel Monkey

In previous studies, we showed that the spatial and intensive aspects of the SI response to skin flutter stimulation are modified systematically as stimulus amplitude is increased. In this study, we examined the effects of duration of skin flutter stimulation on the spatiotemporal characteristics of the response of SI cortex. Optical intrinsic signal (OIS) imaging was used to study the evoked response in SI of anesthetized squirrel monkeys to 25-Hz sinusoidal vertical skin displacement stimulation. Four stimulus durations were tested (0.5, 1.0, 2.0, and 5.0 s); all stimuli were delivered to a discrete site on the glabrous skin of the contralateral forelimb. Skin stimulation evoked a prominent increase in absorbance within the forelimb regions in SI of the contralateral hemisphere. Responses to brief (0.5 s) stimuli were weaker and spatially more extensive than responses to longer duration stimuli (1.0, 2.0, and 5.0 s). Stimuli ≥1 s in duration suppressed responses to below background levels (decreased absorbance) in regions that surrounded the maximally activated region. The magnitude of the suppression in the surrounding regions was nonuniform and usually was strongest medial and posterior to the maximally activated region. The results show that sustained (≥1.0 s) stimulation decreases the spatial extent of the responding SI cortical population. Registration of the optical responses with the previously documented SI topographical organization strongly suggests that the cortical regions that undergo the strongest suppression represent skin sites that are normally co-stimulated during tactile exploration.

Functional Subdomain in the Ankyrin Domain of Tankyrase 1 Required for Poly(ADP-Ribosyl)ation of TRF1 and Telomere Elongation

ABSTRACT In human cells, telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 binds TRF1 via its ankyrin domain and poly(ADP-ribosyl)ates it. Overexpression of tankyrase 1 in telomerase-positive cells releases TRF1 from telomeres, resulting in telomere elongation. The tankyrase 1 ankyrin domain is classified into five conserved subdomains, ARCs (ankyrin repeat clusters) I to V. Here, we investigated the biological significance of the ARCs. First, each ARC worked as an independent binding site for TRF1. Second, ARCs II to V recognized the N-terminal acidic domain of TRF1 whereas ARC I bound a discrete site between the homodimerization and the Myb-like domains of TRF1. Inactivation of TRF1 binding in the C-terminal ARC, ARC V, either by deletion or point mutation, significantly reduced the ability of tankyrase 1 to poly(ADP-ribosyl)ate TRF1, release TRF1 from telomeres, and elongate telomeres. In contrast, other ARCs, ARC II and/or IV, inactivated by point mutations still retained the biological function of tankyrase 1. On the other hand, ARC V per se was not sufficient for telomere elongation, suggesting a structural role for multiple ARCs. This work provides evidence that specific ARC-TRF1 interactions play roles in the essential catalytic function of tankyrase 1.

Two Compound Replication Origins in Saccharomyces cerevisiae Contain Redundant Origin Recognition Complex Binding Sites

ABSTRACT While many of the proteins involved in the initiation of DNA replication are conserved between yeasts and metazoans, the structure of the replication origins themselves has appeared to be different. As typified by ARS1, replication origins inSaccharomyces cerevisiae are <150 bp long and have a simple modular structure, consisting of a single binding site for the origin recognition complex, the replication initiator protein, and one or more accessory sequences. DNA replication initiates from a discrete site. While the important sequences are currently less well defined, metazoan origins appear to be different. These origins are large and appear to be composed of multiple, redundant elements, and replication initiates throughout zones as large as 55 kb. In this report, we characterize two S. cerevisiae replication origins, ARS101 and ARS310, which differ from the paradigm. These origins contain multiple, redundant binding sites for the origin recognition complex. Each binding site must be altered to abolish origin function, while the alteration of a single binding site is sufficient to inactivate ARS1. This redundant structure may be similar to that seen in metazoan origins.