Work

Substituting Threonine 187 with Alanine in p27Kip1 Prevents Pituitary Tumorigenesis by Two-Hit Loss of Rb1 and Enhances Humoral Immunity in Old Age

Year: 2015

Type: article

Abstract: p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases. Inhibiting p27 protein degradation is an actively developing cancer therapy strategy. One focus has been to identify small molecule inhibitors to block recruitment of Thr-187-phosphorylated p27 (p27T187p) to SCF Skp2/Cks1 ubiquitin ligase. Since phosphorylation of Thr-187 is required for this recruitment, p27T187A knockin (KI) mice were generated to determine the effects of systemically blocking interaction between p27 and Skp2/Cks1 on tumor susceptibility and other proliferation related mouse physiology. Rb1 +/− mice develop pituitary tumors with full penetrance and the tumors are invariably Rb1 −/− , modeling tumorigenesis by two-hit loss of RB1 in humans. Immunization induced humoral immunity depends on rapid B cell proliferation and clonal selection in germinal centers (GCs) and declines with age in mice and humans. Here, we show that p27T187A KI prevented pituitary tumorigenesis in Rb1 +/− mice and corrected decline in humoral immunity in older mice following immunization with sheep red blood cells (SRBC). These findings reveal physiological contexts that depend on p27 ubiquitination by SCF Skp2-Cks1 ubiquitin ligase and therefore help forecast clinical potentials of Skp2/Cks1-p27T187p interaction inhibitors. We further show that GC B cells and T cells use different mechanisms to regulate their p27 protein levels, and propose a T helper cell exhaustion model resembling that of stem cell exhaustion to understand decline in T cell-dependent humoral immunity in older age. Background p27T187A knockin mice facilitate studying p27Kip1 protein in physiology. Results p27T187A knockin prevented pituitary tumorigenesis in Rb1 +/− mice and enhanced humoral response to immunization in older age. Conclusion Phosphorylation of p27T187 is important in Rb1 -deficient tumorigenesis and immunity in aging. Significance Specific cancer is identified for treatment by inhibiting Skp2/Cks1-p27T187p interaction and new directions are revealed in understanding immunity decline in elderly.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m114.625350