Randall Division of Cell and Molecular Biophysics

About: Randall Division of Cell and Molecular Biophysics is a based out in . It is known for research contribution in the topics: Actin cytoskeleton & Skeletal muscle. The organization has 576 authors who have published 1229 publications receiving 78279 citations.

Perplexing Pax: From puzzle to paradigm

Abstract: Pax transcription factors are critical for the development of the central nervous system (CNS) where they have a biphasic role, initially dictating CNS regionalization, while later orchestrating differentiation of specific cell subtypes. While a plethora of expression, misexpression, and mutation studies lend support for this argument and clarify the importance of Pax genes in CNS development, less well understood, and more perplexing, is the continued Pax expression in the adult CNS. In this article we explore the mechanism of action of Pax genes in general, and while being cognizant of existing developmental data, we also draw evidence from (1) adult progenitor cells involved in regeneration and tissue maintenance, (2) specific expression patterns in fully differentiated adult cells, and (3) analysis of direct target genes functioning downstream of Pax proteins. From this, we present a more encompassing theory that Pax genes are key regulators of a cell's measured response to a dynamic environment.

Structural changes in troponin in response to Ca2+ and myosin binding to thin filaments during activation of skeletal muscle.

Abstract: Contraction of skeletal and cardiac muscle is regulated by Ca2+-dependent structural changes in troponin that control the interaction between myosin and actin. We measured the orientations of troponin domains in skeletal muscle fibers using polarized fluorescence from bifunctional rhodamine probes on the C and E helices of troponin C. The C helix, in the regulatory head domain, tilts by ≈30° when muscle is activated in physiological conditions, with a Ca2+-sensitivity similar to that of active force. Complete inhibition of active force did not affect C-helix orientation, and binding of rigor myosin heads did not affect its orientation at saturating [Ca2+]. The E helix, in the IT arm of troponin, tilted by ≈10° on activation, and this was reduced to only 3° when active force was inhibited. Binding of rigor myosin heads produced a larger tilt of the E helix. Thus, in situ, the regulatory head acts as a pure Ca2+-sensor, whereas the IT arm is primarily sensitive to myosin head binding. The polarized fluorescence data from active muscle are consistent with an in vitro structure of the troponin core complex in which the D and E helices of troponin C are collinear. The present data were used to orient this structure in the fiber and suggest that the IT arm is at ≈30° to the filament axis in active muscle. In relaxed muscle, the IT arm tilts to ≈40° but the D/E helix linker melts, allowing the regulatory head to tilt through a larger angle.

ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA

Abstract: Long-term survival remains low for most patients with glioblastoma (GBM), which reveals the need for markers of disease outcome and novel therapeutic targets. We describe that ODZ1 (also known as TENM1), a type II transmembrane protein involved in fetal brain development, plays a crucial role in the invasion of GBM cells. Differentiation of glioblastoma stem-like cells drives the nuclear translocation of an intracellular fragment of ODZ1 through proteolytic cleavage by signal peptide peptidase-like 2a. The intracellular fragment of ODZ1 promotes cytoskeletal remodelling of GBM cells and invasion of the surrounding environment both in vitro and in vivo. Absence of ODZ1 by gene deletion or downregulation of ODZ1 by small interfering RNAs drastically reduces the invasive capacity of GBM cells. This activity is mediated by an ODZ1-triggered transcriptional pathway, through the E-box binding Myc protein, that promotes the expression and activation of Ras homolog family member A (RhoA) and subsequent activation of Rho-associated, coiled-coil containing protein kinase (ROCK). Overexpression of ODZ1 in GBM cells reduced survival of xenografted mice. Consistently, analysis of 122 GBM tumour samples revealed that the number of ODZ1-positive cells inversely correlated with overall and progression-free survival. Our findings establish a novel marker of invading GBM cells and consequently a potential marker of disease progression and a therapeutic target in GBM.