Randy Strich

Bio: Randy Strich is an academic researcher from Rowan University. The author has contributed to research in topics: Cyclin & Cyclin A. The author has an hindex of 18, co-authored 37 publications receiving 1065 citations. Previous affiliations of Randy Strich include University of Medicine and Dentistry of New Jersey.

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Abstract: Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.

In vitro biodegradation behavior, mechanical properties, and cytotoxicity of biodegradable Zn-Mg alloy.

Abstract: Zinc–Magnesium (Zn–Mg) alloy as a novel biodegradable metal holds great potential in biodegradable implant applications as it is more corrosion resistant than Magnesium (Mg). However, the mechanical properties, biodegradation uniformity, and cytotoxicity of Zn–Mg alloy remained as concerns. In this study, hot extrusion process was applied to Zn–1 wt % Mg (Zn–1Mg) to refine its microstructure. Effects of hot extrusion on biodegradation behavior and mechanical properties of Zn–1Mg were investigated in comparison with Mg rare earth element alloy WE43. Metallurgical analysis revealed significant grain size reduction, and immersion test found that corrosion rates of WE43 and Zn–1Mg were reduced by 35% and 57%, respectively after extrusion. Moreover, hot extrusion resulted in a much more uniform biodegradation in extruded Zn–1Mg alloy and WE43. In vitro cytotoxicity test results indicated that Zn–1Mg alloy was biocompatible. Therefore, hot extruded Zn–1Mg with homogenous microstructure, uniform as well as slow degradation, improved mechanical properties, and good biocompatibility was believed to be an excellent candidate material for load-bearing biodegradable implant application. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 1632–1640, 2015.

Ama1p is a meiosis-specific regulator of the anaphase promoting complex/cyclosome in yeast

Abstract: Meiosis is the developmental program by which diploid organisms produce haploid gametes capable of sexual reproduction. Here we describe the yeast gene AMA1, a new member of the Cdc20 protein family that regulates the multisubunit ubiquitin ligase termed the anaphase promoting complex/cyclosome (APC/C). AMA1 is developmentally regulated in that its transcription and splicing occur only in meiotic cells. The meiosis-specific processing of AMA1 mRNA depends on the previously described MER1 splicing factor. Several results indicate that Ama1p is required for APC/C function during meiosis. First, coimmunoprecipitation assays indicate that Ama1p associates with the APC/C in vivo. Second, Ama1p is required for the degradation of the B-type cyclin Clb1p, an APC/C substrate in both meiotic and mitotic cells. Third, ectopic overexpression of AMA1 is able to stimulate ubiquitination of Clb1p in vitro and degradation of Clb1p in vivo. Mutants lacking AMA1 revealed that it is required for the first meiotic division but not the mitotic-like meiosis II. In addition, ama1 mutants are defective for both spore wall assembly and the expression of late meiotic genes. In conclusion, this study indicates that Ama1p directs a meiotic APC/C that functions solely outside mitotic cell division. The requirement of Ama1p only for meiosis I and spore morphogenesis suggests a function for APC/CAma1 specifically adapted to germ cell development.

Oxidative-stress-induced nuclear to cytoplasmic relocalization is required for Not4-dependent cyclin C destruction

Abstract: The yeast cyclin-C–Cdk8p kinase complex represses the transcription of a subset of genes involved in the stress response. To relieve this repression, cyclin C is destroyed in cells exposed to H2O2 by the 26S proteasome. This report identifies Not4p as the ubiquitin ligase mediating H2O2-induced cyclin C destruction. Not4p is required for H2O2-induced cyclin C destruction in vivo and polyubiquitylates cyclin C in vitro by utilizing Lys48, a ubiquitin linkage associated with directing substrates to the 26S proteasome. Before its degradation, cyclin C, but not Cdk8p, translocates from the nucleus to the cytoplasm. This translocation requires both the cell-wall-integrity MAPK module and phospholipase C, and these signaling pathways are also required for cyclin C destruction. In addition, blocking cytoplasmic translocation slows the mRNA induction kinetics of two stress response genes repressed by cyclin C. Finally, a cyclin C derivative restricted to the cytoplasm is still subject to Not4p-dependent destruction, indicating that the degradation signal does not occur in the nucleus. These results identify a stress-induced proteolytic pathway regulating cyclin C that requires nuclear to cytoplasmic relocalization and Not4p-mediated ubiquitylation.

The anaphase promoting complex/cyclosome: a machine designed to destroy

Abstract: The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. Recent discoveries have revealed an unexpected multitude of mechanisms that control APC/C activity, and have provided a first insight into how this unusual ubiquitin ligase recognizes its substrates.

Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

Abstract: The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to the Rho1 GTPase, which mobilizes a physiologic response through a variety of effectors. Activation of CWI signaling regulates the production of various carbohydrate polymers of the cell wall, as well as their polarized delivery to the site of cell wall remodeling. This review article centers on CWI signaling in Saccharomyces cerevisiae through the cell cycle and in response to cell wall stress. The interface of this signaling pathway with other pathways that contribute to the maintenance of cell wall integrity is also discussed.

The anaphase-promoting complex: it's not just for mitosis any more

Abstract: The ability of cells to make exact replicas of themselves is central to the life and development of complex organisms. Initial insights into the question of how cells divide came during the latter half of the 19th century when Walther Flemming visualized structures he called threads (which we now call chromosomes) and described how these threads change during cell multiplication, a process he called mitosis. Now, more than a century later, we have a molecular understanding of many of the cellular processes that Flemming observed. Indeed, major cytological events occurring during mitosis are known to constitute cell cycle transitions and are regulated by complex signal transduction pathways whose major components have been identified during the past decade. In this review, we describe recent efforts to understand how central components of this regulatory apparatus—cyclin-dependent kinases and the anaphasepromoting complex/cyclosome (APC/C)—control progression through the cell division cycle and how regulatory mechanisms impinge on the APC/C. The APC/C is the multisubunit ubiquitin ligase whose activity is precisely regulated to ensure the timely degradation of cyclins and other key cell cycle regulators in unperturbed cells and to respond to mitotic checkpoints that prevent their degradation. We pay particular attention to recent developments as excellent reviews are available from a few years ago (Morgan 1999; Zachariae and Nasmyth 1999).

The transcriptional program of meiosis and sporulation in fission yeast.

Abstract: Sexual reproduction requires meiosis to produce haploid gametes, which in turn can fuse to regenerate a diploid organism. We have studied the transcriptional program that drives this developmental process in Schizosaccharomyces pombe using DNA microarrays. Here we show that hundreds of genes are regulated in successive waves of transcription that correlate with major biological events of meiosis and sporulation. Each wave is associated with specific promoter motifs. Clusters of neighboring genes (mostly close to telomeres) are co-expressed early in the process, which reflects a more global control of these genes. We find that two Atf-like transcription factors are essential for the expression of late genes and formation of spores, and identify dozens of potential Atf target genes. Comparison with the meiotic program of the distantly related Saccharomyces cerevisiae reveals an unexpectedly small shared meiotic transcriptome, suggesting that the transcriptional regulation of meiosis evolved independently in both species.