St. Jude Children's Research Hospital

Other

The Johns Hopkins University

Washington University

The United States of America As Represented by the Secretary, Department

Michael B Kastan

Christopher Bakkenist

Albert J Fornace, Jr

Christine Canman

Dae-Sik Lim

Seong-Tae Kim

Masatoshi Takagi

Clay F Semenkovich

Jochen Schneider

Jing Chen

France Carrier

The present invention relates to novel methods for modulating the activity of p53 tumor suppressor protein by affecting p53 translational regulation. More specifically, the invention relates to novel methods for modulating p53 mRNA translation in a cell by affecting a function of a p53 5'-untranslated region (5&#x2032;UTR), including its interaction with proteins such as Ribosomal Protein L26 (RPL26), nucleolin, and p53. The invention also relates to the use of these methods for treating cancer, neurodegenerative disorders and minimizing the negative effects of cellular stresses.

Methods for regulation of p53 translation and function

The present invention relates to novel oligonucleotides which comprise p53 5'-UTR sequence TCCCTGG (SEQ ID NO: 1) or the complementary p53 3&#x2032;-UTR sequence CCAGGGA (SEQ ID NO: 2) and their use for such therapeutic applications as protection of normal tissues from the toxicities of chemical or radiation exposure; reducing tissue damage in hypoxia-reperfusion injury, neurodegenerative disorders, oxidative stress, injuries, hyperthermia; preventing aging; preservation of tissues and organs prior to transplanting, etc.

Oligonucleotides which inhibit p53 induction in response to cellular stress

The present invention provides methods and compositions for modulating certain metabolic processes and for treating a variety of disorders associated with metabolic syndrome, including insulin related disorders, ischemia, oxidative stress, atherosclerosis, hypertension, obesity, abnormal lipid metabolism, and stroke by administering an effective dose of a chloroquine compound. The invention also provides methods and compositions relating to administering an effective dose of a chloroquine compound in combination with at least a second pharmaceutically active ingredient or compound including an antihyperglycemic diabetes treatment, an antihypertensive agent, an antithrombotic agent, and/or an inhibitor of cholesterol synthesis or absorption.

Use of chloroquine to treat metabolic syndrome

The present invention provides methods for detecting activation of ATM kinase, DNA damage, and DNA damaging agents. Further provided are antibodies which specifically recognize the phosphorylation state of Ataxia Telangiectasia-Mutated (ATM) kinase. Methods of identifying agents which modulate the activation and activity of ATM kinase are also provided.

ATM kinase compositions and methods

The present invention relates to identification of the consensus sequence phosphorylated by ATM kinase. This, in turn, permitted identification of ATM kinase target proteins, and development of a convenient assay system for ATM kinase phosphorylation using fusion polypeptides as substrates. The assay system is adaptable to screening for ATM modulators, particularly inhibitors. In a specific embodiment, the substrate recognition sequence and mutagenized variants of this sequence were incorporated in a GST fusion protein and assayed for phosphorylation by ATM kinase. This assay system is useful in screening for ATM inhibitors. ATM function assays were validated using an ATM-kinase dead dominant-negative mutant.

ATM kinase modulation for screening and therapies

Method for determining the presence of functional p53 by measuring

The dependence of ionizing radiation-induced GADD45 mRNA expression on the presence of functional p53 in mammalian cells is disclosed. First and second oligonucleotide sequences are provided which can form a double-stranded oligomer capable of binding to functional p53 protein. The present invention demonstrates that the dependence of ionizing radiation-induced GADD45 mRNA expression on the presence of functional p53 and the binding of functional p53 to a double-stranded oligomer binding sequence can serve as the basis for methods for determining the presence of functional p53 in mammalian cell lines and tumors.

Growing community of inventors

Cordova, TN, United States of America

Michael B Kastan