Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1(-/-) mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1(WT) or cyclin D1(KE) in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1(KE) induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1(WT) and cyclin D1(KE) to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis

Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis.

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis

Inhomogeneous tachyon dynamics and the zipper

We study the process of inhomogeneous tachyon condensation in an intersecting D1- and anti-D1-brane system using an effective tachyon DBI action. By switching to the Hamiltonian formalism, we numerically solve for the dynamical evolution of the system at a small intersection angle. We find that the decay proceeds indefinitely and resembles the action of two zippers moving away from the intersection point at the speed of light, zipping the branes together and leaving inhomogeneous tachyon matter behind. We also discuss the range of validity of our analysis and discuss the relation of the D1-anti-D1 description of the system to one in terms of an intersecting D1-D1-brane pair.Comment: 23 pages, 12 figures. v2: added references; v3: more references, published versio

Origin and evolution of water oxidation before the last common ancestor of the Cyanobacteria

Photosystem II, the water oxidizing enzyme, altered the course of evolution by filling the atmosphere with oxygen. Here, we reconstruct the origin and evolution of water oxidation at an unprecedented level of detail by studying the phylogeny of all D1 subunits, the main protein coordinating the water oxidizing cluster (Mn4CaO5) of Photosystem II. We show that D1 exists in several forms making well-defined clades, some of which could have evolved before the origin of water oxidation and presenting many atypical characteristics. The most ancient form is found in the genome of Gloeobacter kilaueensis JS-1 and this has a C-terminus with a higher sequence identity to D2 than to any other D1. Two other groups of early evolving D1 correspond to those expressed under prolonged far-red illumination and in darkness. These atypical D1 forms are characterized by a dramatically different Mn4CaO5 binding site and a Photosystem II containing such a site may assemble an unconventional metal cluster. The first D1 forms with a full set of ligands to the Mn4CaO5 cluster are grouped with D1 proteins expressed only under low oxygen concentrations and the latest evolving form is the dominant type of D1 found in all cyanobacteria and plastids. In addition, we show that the plastid ancestor had a D1 more similar to those in early branching Synechococcus. We suggest each one of these forms of D1 originated from transitional forms at different stages towards the innovation and optimization of water oxidation before the last common ancestor of all known cyanobacteria

On singular moduli for arbitrary discriminants

Let d1 and d2 be discriminants of distinct quadratic imaginary orders O_d1 and O_d2 and let J(d1,d2) denote the product of differences of CM j-invariants with discriminants d1 and d2. In 1985, Gross and Zagier gave an elegant formula for the factorization of the integer J(d1,d2) in the case that d1 and d2 are relatively prime and discriminants of maximal orders. To compute this formula, they first reduce the problem to counting the number of simultaneous embeddings of O_d1 and O_d2 into endomorphism rings of supersingular curves, and then solve this counting problem. Interestingly, this counting problem also appears when computing class polynomials for invariants of genus 2 curves. However, in this application, one must consider orders O_d1 and O_d2 that are non-maximal. Motivated by the application to genus 2 curves, we generalize the methods of Gross and Zagier and give a computable formula for v_p(J(d1,d2)) for any distinct pair of discriminants d1,d2 and any prime p>2. In the case that d1 is squarefree and d2 is the discriminant of any quadratic imaginary order, our formula can be stated in a simple closed form. We also give a conjectural closed formula when the conductors of d1 and d2 are relatively prime.Comment: 33 pages. Changed the abstract and made small changes to the introduction. Reorganized section 3.2, 4, and proof of Proposition 8.1. Some remarks added to section

Supersymmetric Giant Graviton Solutions in AdS_3

We parameterize all classical probe brane configurations that preserve 4 supersymmetries in (a) the extremal D1-D5 geometry, (b) the extremal D1-D5-P geometry, (c) the smooth D1-D5 solutions proposed by Lunin and Mathur and (d) global $AdS_3 \times S_3 \times T^4/K3$. These configurations consist of D1 branes, D5 branes and bound states of D5 and D1 branes with the property that a particular Killing vector is tangent to the brane worldvolume at each point. We show that the supersymmetric sector of the D5 brane worldvolume theory may be analyzed in an effective 1+1 dimensional framework that places it on the same footing as D1 branes. In global AdS and the corresponding Lunin-Mathur solution, the solutions we describe are `bound' to the center of AdS for generic parameters and cannot escape to infinity. We show that these probes only exist on the submanifold of moduli space where the background $B_{NS}$ field and theta angle vanish. We quantize these probes in the near horizon region of the extremal D1-D5 geometry and obtain the theory of long strings discussed by Seiberg and Witten.Comment: 63 page

Brane Intersections in the Presence of a Worldvolume Electric Field

The study of brane intersections has provided important insights into a possible non-commutative structure of spacetime geometry. In this paper we focus on the D1$\bot$D3 system. We compare the D1 and D3 descriptions of the interesection and search for non-static solutions of the D3$\bot$D1 funnel equations in the presence of a worldvolume electric field. We find that the D1 and D3 descriptions do not agree. We find time dependent solutions that are a natural generalization of those found without the electric field.Comment: 10 page

Tachyon condensation and `bounce' in the D1-D5 system

We construct supergravity solutions dual to microstates of the D1-D3-D5 system with nonzero B field moduli. Just like the D1-D5 solutions in hep-th/0109154 these solutions are generically nonsingular everywhere, with the `throat' closing smoothly near r=0. We write expressions relating the asymptotic supergravity fields to the integral brane charges. We study the infall of a D1 brane down the throat of the geometries. This test brane `bounces' off the smooth end for generic initial conditions. The details of the bounce depend on both the choice of D1-D3-D5 microstate and the direction of approach of the infalling D1 brane. In the dual field theory description we see that the tachyon mode starts to condense, but the tachyon bounces back up the potential hill without reaching the deepest point of the potential.Comment: 32 pages, references adde

Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes. Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3\u27UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling