| First Author | Zhao H | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 9 | Pages | 5797-809 |
| PubMed ID | 25583987 | Mgi Jnum | J:251068 |
| Mgi Id | MGI:6102021 | Doi | 10.1074/jbc.M114.625350 |
| Citation | Zhao H, et al. (2015) Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age. J Biol Chem 290(9):5797-809 |
| abstractText | 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. |
