title: Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age.
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.
authors.affiliation: From the Department of Developmental and Molecular Biology, and Medicine, and.
authors.forename: Hongling
authors.initials: H
authors.lastname: Zhao
authors.affiliation: From the Department of Developmental and Molecular Biology, and Medicine, and.
authors.forename: Frederick
authors.initials: F
authors.lastname: Bauzon
authors.affiliation: Cell Biology, and.
authors.forename: Enguang
authors.initials: E
authors.lastname: Bi
authors.affiliation: Cell Biology, and.
authors.forename: J Jessica
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: From the Department of Developmental and Molecular Biology, and Medicine, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Fu
authors.affiliation: From the Department of Developmental and Molecular Biology, and Medicine, and.
authors.forename: Zhonglei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: From the Department of Developmental and Molecular Biology, and Medicine, and.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Cui
authors.affiliation: Microbiology and Immunology, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Jeon
authors.affiliation: Microbiology and Immunology, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
authors.affiliation: Cell Biology, and.
authors.forename: B Hilda
authors.initials: BH
authors.lastname: Ye
authors.affiliation: From the Department of Developmental and Molecular Biology, and Medicine, and liang.zhu@einstein.yu.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000367:Age Factors; D000409:Alanine / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics* / Q000276:immunology; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D012756:Sheep; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013912:Threonine; D044843:SKP Cullin F-Box Protein Ligases; D000409:Alanine
keywords: aging; germinal center; humoral immunity; immunization; p27Kip1; phosphorylation; pituitary gland; retinoblastoma protein (pRb, RB); tumor