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.

Retinoic acid is both necessary for and inhibits myogenic commitment and differentiation in the chick limb.

Abstract: Retinoic acid (RA) plays an essential role in the development of many embryonic tissues, including the developing tetrapod limb bud. At early stages of limb development, RA levels are highest proximally and regulate the migration of myoblasts into the limb. As the premyogenic progenitor cells migrate into the limb and accumulate in premuscle masses, they express Pax3 and Meox2. Myogenic differentiation is initiated by expression of Myf5 and MyoD, and both Pax3 and Meox2 are required for normal Myf5 expression. We show by loss of function using the inhibitor citral, that RA signalling within the limb bud is required to maintain Pax3 and Meox2 in the progenitor and Myf5 and MyoD in the differentiating myoblasts. Treatment with excess RA showed a differential effect: Meox2 and Pax3 showed localised down-regulation of expression in the limb. In contrast, there was a dramatic down-regulation of expression of MyoD, Myf5 and Meox1. The down-regulation of myogenic gene expression in response to inhibition of RA signalling, and differential response to application of excess RA, in the absence of changes to cell proliferation and apoptosis, indicate that myogenic specification and differentiation in the developing limb possess a complex sensitivity to RA concentrations.

Protein–protein interaction networks studies and importance of 3D structure knowledge

Abstract: Protein-protein interaction networks (PPINs) are a powerful tool to study biological processes in living cells. In this review, we present the progress of PPIN studies from abstract to more detailed representations. We will focus on 3D interactome networks, which offer detailed information at the atomic level. This information can be exploited in understanding not only the underlying cellular mechanisms, but also how human variants and disease-causing mutations affect protein functions and complexes' stability. Recent studies have used structural information on PPINs to also understand the molecular mechanisms of binding partner selection. We will address the challenges in generating 3D PPINs due to the restricted number of solved protein structures. Finally, some of the current use of 3D PPINs will be discussed, highlighting their contribution to the studies in genotype-phenotype relationships and in the optimization of targeted studies to design novel chemical compounds for medical treatments.

Functional impact of cancer-associated mutations in the tumor suppressor protein ING4.

Abstract: Inhibitor of growth 4 (ING4) is a member of the ING family of tumor suppressor proteins. In this study, we have analyzed the impact of two mutations in ING4 associated with human tumors (Y121N and N214D), testing their behavior in a series of functional, biochemical and structural analyses. We report that the N214D mutation dramatically dampened the ability of ING4 to inhibit proliferation, anchorage-independent growth or cell migration or to sensitize to cell death. In turn, the Y121N mutant did not differ significantly from wild-type ING4 in our assays. Neither of the mutations altered the normal subcellular localization of ING4, showing predominantly nuclear accumulation. We investigated the molecular basis of the defect in the activity of the N214D mutant. The folding and ability to bind histone marks of ING4 was not significantly altered by this mutation. Instead, we found that the functional impairment of the N214D mutant correlates with reduced protein stability due to increased proteasome-mediated degradation. In summary, our data demonstrates that a point mutation of ING4 associated to human tumors leads to the loss of several essential functions of ING4 pertinent to tumor protection and highlight the importance of ING4 function to prevent tumorigenesis.

Curvature-induced expulsion of actomyosin bundles during cytokinetic ring contraction

Abstract: Many eukaryotes assemble a ring-shaped actomyosin network that contracts to drive cytokinesis. Unlike actomyosin in sarcomeres, which cycles through contraction and relaxation, the cytokinetic ring disassembles during contraction through an unknown mechanism. Here we find in Schizosaccharomyces japonicus and Schizosaccharomyces pombe that, during actomyosin ring contraction, actin filaments associated with actomyosin rings are expelled as micron-scale bundles containing multiple actomyosin ring proteins. Using functional isolated actomyosin rings we show that expulsion of actin bundles does not require continuous presence of cytoplasm. Strikingly, mechanical compression of actomyosin rings results in expulsion of bundles predominantly at regions of high curvature. Our work unprecedentedly reveals that the increased curvature of the ring itself promotes its disassembly. It is likely that such a curvature-induced mechanism may operate in disassembly of other contractile networks.