Various publications, including patents, published applications, accession numbers, technical articles and scholarly articles are cited throughout the specification. Each cited publication is incorporated by reference herein, in its entirety and for all purposes.
The tumor suppressor p16lnk4a mediates cell cycle arrest and senescence in vitro, constrains proliferation of some aging progenitors cells, and is widely used as a marker of cellular senescence and aging in vivo. However, whether p16 expression is sufficient to confer cell cycle arrest, senescence, or aging features in vivo is unknown.
Induction of p16 in tumors arising in situ can test whether inhibition of its target cyclin dependent kinases (cdk) can block growth of such tumors. Cdk inhibitors are being broadly developed by the pharmaceutical industry for cancer chemotherapy. However, whether inhibition of cdks can block tumor growth is unknown.
p16lnk4a has been known to the research community for nearly 20 years, but a p16-inducible mouse has not previously been generated. On the one hand, some published data questions whether p16 would block growth of cells in the animal. On the other hand, prior to the experiments described herein, it might have been expected that mice with p16 induction would die promptly, making them unsuitable for many experiments.
There is a need to produce p16 transgenes with an inducible activator expressed in a tissue-specific fashion to avoid potential morbidity and mortality from p16 expression.