Mitotix, Inc.

Gpc Biotech, Inc.

Giulio Draetta

Guillaume Cottarel

Mark Rolfe

Veronique Damagnez

Jeno Gyuris

Vivian Berlin

Maria Isabel Chiu

Lou Lamphere

Peggy L Beer-Romero

Jens W Eckstein

The present invention relates to the discovery in eukaryotic cells, particularly human cells, of novel protein-protein interactions between certain cellular proteins, referred to herein as 'E6AP-binding proteins' or 'E6AP-BPs', and the cellular protein E6AP, the latter of which is a component of a ubiquitin-ligase (E3) enzyme. The association of E6AP and the subject E6AP-binding proteins implicates the E6AP-binding proteins in a number of basic cellular functions, such as regulation of gene expression, regulation of the cell-cycle, modification of cell surface receptors, biogenesis of ribosomes, and DNA repair. One of the E6AP-binding proteins shares certain homology with the papillomavirus E6 protein, which also binds E6AP.

E6AP-binding proteins

The present invention makes available assays and reagents for identifying anti-proliferative agents, such as mitotic and meiotic inhibitors. The present assay provides a simple and rapid screening test which relies on scoring for positive cellular proliferation as indicative of anti-mitotic or anti-meiotic activity, and comprises contacting a candidate agent with a cell which has an impaired cell-cycle checkpoint and measuring the level of proliferation in the presence and absence of the agent. The checkpoint impairment is such that it either causes premature progression of the cell through at least a portion of a cell-cycle or inhibition of normal progression of the cell through at least a portion of a cell-cycle, but can be off-set by the action of an agent which inhibits at least one regulatory protein of the cell-cycle in a manner which counter-balances the effect of the impairment.

Assay and reagents for identifying anti-proliferative agents

The present invention relates to drug screening assays which provide a systematic and practical approach for the identification of candidate agents able to inhibit ubiquitin-mediated degradation of a cell-cycle regulatory protein, such as p53, p27, myc, fos, MAT.alpha.2, or cyclins. The invention further relates to novel ubiquitin-conjugating enzymes, and uses related thereto.

Ubiquitin conjugating enzymes

The present invention relates to the discovery in mammalian cells, particularly human cells, of a novel CDK-binding protein, referred to herein as 'cdc37'. As described herein, this protein functions to facilitate activation and accordingly finctions in the modulation of cell-cycle progression, and therefore ultimately of cell growth and differentiation. Moreover, binding data indicated that cdc37 may function coordinately with other cell-cycle regulatory proteins, such as of cyclin-dependent kinases (CDKs), src, p53 and erk kinases.

CDC37 cell-cycle regulatory protein and uses related thereto

The present invention concerns a novel human ubiquitin-conjugating enzyme which is implicated in the ubiquitin-mediated inactivation of cell-cycle regulatory proteins, partucularly p53. The present invention makes available diagnostic and therapeutic assays and reagents for detecting and treating transformed cells, such as may be useful in the detection of cancer. The present invention also provides reagents for altering the normal regulation cell proliferation in untransformed cells, such as by upregulating certain cell-cycle checkpoints, e.g. to protect normal cells against DNA damaging reagents.

Human ubiquitin conjugating enzyme

The present invention relates to the discovery that antisense nucleic acids complimentary to an E6AP gene can be used to regulate cellular p53 levels. In general the invention features E6AP antisense constructs which, by inhibiting E6AP activity, can modulate cellular p53 levels in both p53+ transformed cells and in normal cells. The invention also provides methods for treating papillomavirus (PV) induced condition, methods for regulating cellular p53 levels and methods for regulating cellular proliferation.

E6AP antisense constructs and methods of use

The present invention relates to the discovery of novel cell cycle regulatory proteins from the human pathogen Candida.

Nucleic acid encoding a Candida cell cycle regulatory protein, TYP1

The present invention relates to the discovery in mammalian cells, particularly human cells, of a novel CDK-binding protein, referred to herein as 'cdc37'. As described herein, this protein functions to facilitate activation and accordingly functions in the modulation of cell-cycle progression, and therefore ultimately of cell growth and differentiation. Moreover, binding data indicated that cdc37 may function coordinately with other cell-cycle regulatory proteins, such as of cyclin-dependent kinases (CDKs), src, p53 and erk kinases.

CDC37 cell-cycle regulatory protein, and uses related thereto

The present invention concerns three ubiquitin-conjugating enzymes.

The present invention relates to the discovery of novel proteins of mammalian origin which can associate with the human cyclin dependent kinase 4 (CDK4).

CDK4 binding assay

The present invention makes available assays and reagents for identifying anti-proliferative agents, such as mitotic and meiotic inhibitors, especially inhibitors of cdc25 phosphatase. The present assay provides a simple and rapid screening test which relies on scoring for positive cellular proliferation as indicative of anti-mitotic or anti-meiotic activity, and comprises contacting a candidate agent with a cell which has an impaired cell-cycle checkpoint and measuring the level of proliferation in the presence and absence of the agent. The checkpoint impairment is such that it either causes premature progression of the cell through at least a portion of a cell-cycle or inhibition of normal progression of the cell through at least a portion of a cell-cycle, but can be off-set by the action of an agent which inhibits at least one regulatory protein of the cell-cycle in a manner which counter-balances the effect of the impairment.

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Winchester, MA, United States of America

Giulio Draetta