Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane

Heparin-binding EGF-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein (proHB-EGF) and expressed on the cell surface. The ectodomain shedding of proHB-EGF at the extracellular region on the plasma membrane yields a soluble EGF receptor ligand and a transmembrane-cytoplasmic fragment (HB-EGF-CTF). The cytoplasmic domain of proHB-EGF (HB-EGF-cyto) interacts with transcriptional repressors to reverse their repressive activities. However, how HB-EGF-cyto accesses transcriptional repressors is yet unknown. The present study demonstrates that, after exposure to shedding stimuli, both HB-EGF-CTF and unshed proHB-EGF translocate to the nuclear envelope. Immunoelectron microscopy and digitonin-permeabilized cells showed that HB-EGF-cyto signals are at the inner nuclear membrane. A short sequence element within the HB-EGF-cyto allows a transmembrane protein to localize to the nuclear envelope. The dominant-active form of Rab5 and Rab11 suppressed nuclear envelope targeting. Collectively, these data demonstrate that membrane-anchored HB-EGF is targeted to the inner nuclear membrane via a retrograde membrane trafficking pathway

Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity

INTRODUCTION: Loss of histone H4 lysine 20 trimethylation (H4K20me3) is associated with multiple cancers, but its role in breast tumors is unclear. In addition, the pathological effects of global reduction in H4K20me3 remain mostly unknown. Therefore, a major goal of this study was to elucidate the global H4K20me3 level in breast cancer tissue and investigate its pathological functions. METHODS: Levels of H4K20me3 and an associated histone modification, H3 lysine 9 trimethylation (H3K9me3), were evaluated by immunohistochemistry in a series of breast cancer tissues. Univariate and multivariate clinicopathological and survival analyses were performed. We also examined the effect of overexpression or knockdown of the histone H4K20 methyltransferases, SUV420H1 and SUV420H2, on cancer-cell invasion activity in vitro. RESULTS: H4K20me3, but not H3K9me3, was clearly reduced in breast cancer tissue. A reduced level of H4K20me3 was correlated with several aspects of clinicopathological status, including luminal subtypes, but not with HER2 expression. Multivariate analysis showed that reduced levels of H4K20me3 independently associated with lower disease-free survival. Moreover, ectopic expression of SUV420H1 and SUV420H2 in breast cancer cells suppressed cell invasiveness, whereas knockdown of SUV420H2 activated normal mammary epithelial-cell invasion in vitro. CONCLUSIONS: H4K20me3 was reduced in cancerous regions of breast-tumor tissue, as in other types of tumor. Reduced H4K20me3 level can be used as an independent marker of poor prognosis in breast cancer patients. Most importantly, this study suggests that a reduced level of H4K20me3 increases the invasiveness of breast cancer cells in a HER2-independent manner

Signal Transduction across the Nuclear Envelope: Role of the LINC Complex in Bidirectional Signaling

The primary functions of the nuclear envelope are to isolate the nucleoplasm and its contents from the cytoplasm as well as maintain the spatial and structural integrity of the nucleus. The nuclear envelope also plays a role in the transfer of various molecules and signals to and from the nucleus. To reach the nucleus, an extracellular signal must be transmitted across three biological membranes: the plasma membrane, as well as the inner and outer nuclear membranes. While signal transduction across the plasma membrane is well characterized, signal transduction across the nuclear envelope, which is essential for cellular functions such as transcriptional regulation and cell cycle progression, remains poorly understood. As a physical entity, the nuclear envelope, which contains more than 100 proteins, functions as a binding scaffold for both the cytoskeleton and the nucleoskeleton, and acts in mechanotransduction by relaying extracellular signals to the nucleus. Recent results show that the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which is a conserved molecular bridge that spans the nuclear envelope and connects the nucleoskeleton and cytoskeleton, is also capable of transmitting information bidirectionally between the nucleus and the cytoplasm. This short review discusses bidirectional signal transduction across the nuclear envelope, with a particular focus on mechanotransduction

Implications for Diverse Functions of the LINC Complexes Based on the Structure

The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the outer and inner nuclear membrane protein families Klarsicht, Anc-1, and Syne homology (KASH), and Sad1 and UNC-84 (SUN) homology domain proteins. Increasing evidence has pointed to diverse functions of the LINC complex, such as in nuclear migration, nuclear integrity, chromosome movement and pairing during meiosis, and mechanotransduction to the genome. In metazoan cells, the nuclear envelope possesses the nuclear lamina, which is a thin meshwork of intermediate filaments known as A-type and B-type lamins and lamin binding proteins. Both of lamins physically interact with the inner nuclear membrane spanning SUN proteins. The nuclear lamina has also been implicated in various functions, including maintenance of nuclear integrity, mechanotransduction, cellular signalling, and heterochromatin dynamics. Thus, it is clear that the LINC complex and nuclear lamins perform diverse but related functions. However, it is unknown whether the LINC complex–lamins interactions are involved in these diverse functions, and their regulation mechanism has thus far been elusive. Recent structural analysis suggested a dynamic nature of the LINC complex component, thus providing an explanation for LINC complex organization. This review, elaborating on the integration of crystallographic and biochemical data, helps to integrate this research to gain a better understanding of the diverse functions of the LINC complex

Vascular flora of Serra do Japi Biological Reserve, Jundiaí, southeastern Brazil

Floristic sampling was carried out in Serra do Japi Biological Reserve, Jundiaí, state of São Paulo, Brazil, including physiognomies of semideciduous montane forest, a type of forest formation within the Atlantic Forest domain. Six hundred and sixty one species distributed in 129 families were recorded; the ten most diverse phanerogam families were: Asteraceae (56 species), Fabaceae (37), Rubiaceae (29), Poaceae (25), Solanaceae (24), Cyperaceae (19), Euphorbiaceae (19), Orchidaceae (19), Melastomataceae (17), and Piperaceae (17). The addition of 322 species from other floristic surveys increased the number of species of Serra do Japi to 976, distributed in 141 families. Compared to other floristic surveys carried out in the Atlantic Forest, our results highlight the floristic diversity of the study area and the importance of preserving the vegetation of this highly urbanized region