Cold Spring Harbor Laboratory

Other

National Institutes of Health

Konstantin Galaktionov

David H Beach

Catherine Jessus

Two previously undescribed human cdc25 genes, designated cdc25 A and cdc25 B, which have been shown to have an endogenous tyrosine phosphatase activity that can be specifically activated by B-type cyclin, in the complete absence of cdc2 are described. As a result of this work, new approaches to regulating the cell cycle in eukaryotic cells and, particularly, to regulating the activity of tyrosine specific phosphatases which play a key role in the cell cycle are available. Applicant's invention relates to methods of regulating the cell cycle and, specifically, to regulating activation of cdc2-kinase, through alteration of the activity and/or levels of tyrosine phosphatases or through alteration of the interaction of components of MPF. More specifically, the invention relates to inhibiting transcription or translation of mammalian CDC25A genes using oligonucleotides.

Cdc25 genes, encoded products and uses thereof

The present invention makes available assays and reagents for identifying agents which can be used to modulate at least one proliferation, differentiation and cell death by apoptosis.

Assays and reagents for identifying modulators of Cdc25-mediated mitotic activation

The present invention derives from the discovery that CDC25 phosphatases and Raf proteins are able to physically interact to form protein-protein complexes, with the Raf protein mediating the activation of CDC25 phosphatases. The present invention provides both cell-free and cellular assays for detecting agents which modulate the ras-dependent activation of CDC25, as for example, by affecting the binding of a CDC25 protein with Raf, or Raf-associated complexes. Also disclosed is a method for transforming/immortalizing cells, particularly primary cell cultures.

Interactions between RaF proto-oncogenes and CDC25 phosphatases, and

Two previously undescribed human cdc25 genes, designated cdc25 A and cdc25 B, which have been shown to have an endogenous tyrosine phosphatase activity that can be specifically activated by B-type cyclin, in the complete absence of cdc2 are described. As a result of this work, new approaches to regulating the cell cycle in eukaryotic cells and, particularly, to regulating the activity of tyrosine specific phosphatases which play a key role in the cell cycle are available. Applicant's invention relates to methods of regulating the cell cycle and, specifically, to regulating activation of cdc2-kinase, through alteration of the activity and/or levels of tyrosine phosphatases or through alteration of the interaction of components of MPF. The present invention also relates to agents or compositions useful in the method of regulating (inhibiting or enhancing) the cell cycle. Such agents or compositions can be inhibitors (such as low molecular weight peptides or compounds, either organic or inorganic) of the catalytic activity of tyrosine specific PTPases (particularly cdc25), blocking agents which interfere with interaction or binding of the tyrosine specific PTPase with cyclin or the cyclin/cdc2 complex, or agents which interfere directly with the catalytic activity of the PTPases. The invention also pertains to an assay for identifying agents which after stimulation of kinase activity of pre-MPF and thus alter activation of MPF and entry into mitosis. Such agents are also the subject of this invention.

Human cdc25 genes, encoded products and uses thereof

Assays and reagents for identifying modulators of cdc25-mediated mitotic

Nucleic acids encoding cdc25 A and cdc25 B proteins and method of making

CDC25A and CDC25B proteins, fusion proteins thereof, and antibodies

A method of identifying compounds or molecules which alter (enhance or inhibit) stimulation of kinase activity of pre-MPF and, thus, alter (enhance or inhibit) activation of MPF and entry into mitosis. The present method thus makes it possible to identify compounds or molecules which can be administered to regulate the cell cycle; such compounds are also the subject of this invention.

Method of screening for antimitotic compounds using the cdc25 tyrosine

Two previously undescribed human cdc25 genes, designated cdc25 A and cdc25 B, which have been shown to have an endogenous tyrosine phosphatase activity that can be specifically activated by B-type cyclin, in the complete absence of cdc2. As a result of the work described herein, new approaches to regulating the cell cycle in eukaryotic cells and, particularly, to regulating the activity of tyrosine specific phosphatases which play a key role in the cell cycle are available. Applicant's invention relates to methods of regulating the cell cycle and, specifically, to regulating activation of cdc2-kinase, through alteration of the activity and/or levels of tyrosine phosphatases, particularly cdc25 phosphatase, and B-type cyclin or through alteration of the interaction of components of MPF, particularly the association of cdc25 with cyclin, cdc2 or the cdc2/cyclin B complex. The present invention also relates to agents or compositions useful in the method of regulating (inhibiting or enhancing) the cell cycle. Such agents or compositions are, for example, inhibitors (such as low molecular weight peptides or compounds, either organic or inorganic) of the catalytic activity of tyrosine specific PTPases (particularly cdc25), blocking agents which interfere with interaction or binding of the tyrosine specific PTPase with cyclin or the cyclin/cdc2 complex, or agents which interfere directly with the catalytic activity of the PTPases.

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Cold Spring Harbor, NY, United States of America

Konstantin Galaktionov