St. Jude Children's Research Hospital

Frederique Zindy

Martine F Roussel

Charles J Sherr

Dawn E Quelle

Richard Jay Smeyne

Justine Cunningham

Ping Chen

Jason D Weber

Neil Segil

Non-human animals that have been manipulated so as not to express a functional p19 and p27 proteins are described. One particular non-human animal exemplified is a p19 -double null, p27 -double null mouse. Such knockout mice exhibit bradykinesia, proprioceptive abnormalities, seizure-like activity, and generally die 14-24 days after birth. In addition, mammalian cells having the p19 -double null, p27 -double null genotype are characterized. Methods of making and using the non-human knockout animals and cells are disclosed.

Cells that lack p19ink4d and p27kip1 activity and methods of use thereof

The INK4A (MTS1, CDKN2) gene encodes a specific inhibitor (InK4a-p16) of the cyclin D-dependent kinases CDK4 and CDK6. InK4a-p16 can block these kinase from phosphorylating the retinoblastoma protein (pRb), preventing exit from the G1 phase of the cell cycle. Deletions and mutations involving the gene encoding InK4a-p16, INK4A, occur frequently in cancer cells, implying that INK4a-p16, like pRb, suppresses tumor formulation. However, a completely unrelated protein (ARF-p19) arises in major part from an alternative reading frame of the mouse INK4A gene. Expression of an ARF-p19 cDNA (SEQ ID NO:1) in rodent fibroblasts induces both G1 and G2 phase arrest. Economical reutilization of protein coding sequences in this manner is without precedent in mammalian genomes, and the unitary inheritance of INK4a-p16 and ARF-p19 may reflect a dual requirement for both proteins in cell cycle control.

ARF-P19, a novel regulator of the mammalian cell cycle

Non-human animals that have been manipulated so as not to express a functional p19,and p27,proteins are described. One particulat non-human animal exemplified is a p19,-double null, p27,-double null mouse. Such knockout mice exhibit bradykinesia, proprioceptive abnormalties, seizure-like activity, and generally die 14-24 days after birth. In addition, mammalian cells having the p19,-double null, p27,-double null genotype are characterized. Methods of making and using the non-human knockout animals and cells are disclosed.

Knockout mice and cells that lack p19INK4d and p27KIP1 activity and methods of use thereof

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Memphis, TN, United States of America

Frederique Zindy