St. Jude Children's Research Hospital

Vincent J Kidd

Jill M Lahti

Tal Teitz

The present invention relates to identification of tumor suppressor activity of a protein, caspase-8 (CASP8), and to related diagnostic and therapeutic compositions and methods. The discovery of this tumor suppressor activity provides screening targets as well, particularly screening for compounds that overcome gene inactivation that results from genomic methylation of the promoter. In particular, CASP8 is functionally inactivated in greater than 90% of all MYCN amplified neuroblastoma cell lines analyzed. Inactivation of CASP8 was observed to occur by homozygous deletion, heterozygous deletion coupled with gene silencing by methylation, and homozygous gene silencing by methylation. A PCR methylation analysis for inactivation of CASP8 is described.

Tumor suppressor protein involved in death signaling, and diagnostics, therapeutics, and screening based on this protein

The present invention includes alternatively and partially spliced cyclin C mRNAs, recombinant DNA and the truncated protein (a truncated cyclin C) they encode. The alternatively spliced mRNAs result from an insertion of unique exons containing premature termination codons. The partially spliced mRNAs result from an insertion of additional coding sequence derived from exons. One aspect of the present invention is the demonstration that at least one of the alternatively spliced cyclin C mRNAs is produced in a cell cycle dependent fashion, as is the novel truncated cyclin box protein that it encodes. Truncated cyclin C acts as an endogenously encoded cyclin C inhibitor by negatively regulating cyclin C/cdk8 complex activity, in much the same way as the cyclin dependent protein kinase inhibitors that inhibit the D-type cyclins, cyclin A and cyclin E.

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Memphis, TN, United States of America

Vincent J Kidd