title: Dysregulation of the Bmi-1/p16(Ink⁴a) pathway provokes an aging-associated decline of submandibular gland function.
abstract: Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16(Ink4a) . Therefore, dysregulation of the Bmi-1/p16(Ink4a) pathway is considered key to the loss of tissue homeostasis and development of associated degenerative diseases during aging. However, because Bmi-1 knockout (KO) mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16(Ink4a) pathway occurs during aging in vivo. Using real-time in vivo imaging of p16(Ink4a) expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi-1/p16(Ink4a) pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity. This pathway is dysregulated during aging in vivo, leading to induction of p16(Ink4a) expression and subsequent declined SMG function. These findings will advance our understanding of the molecular mechanisms underlying the aging-related decline of SMG function and associated salivary gland hypofunction, which is particularly problematic among the elderly.
authors.affiliation: Department of Mechanism of Aging, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Kimi
authors.initials: K
authors.lastname: Yamakoshi
authors.affiliation: Department of Mechanism of Aging, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Katano
authors.affiliation: Department of Mechanism of Aging, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Mechanism of Aging, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okuma
authors.affiliation: Department of Regenerative Medicine, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Ikemoto-Uezumi
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohtani
authors.affiliation: Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.affiliation: Department of Mechanism of Aging, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Maruyama
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006706:Homeostasis; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063150:Polycomb Repressive Complex 1 / Q000172:deficiency / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D012463:Saliva / Q000378:metabolism; D015398:Signal Transduction; D013363:Submandibular Gland / Q000378:metabolism* / Q000473:pathology
chemical_list: C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D008156:Luciferases; D063150:Polycomb Repressive Complex 1
keywords: Bmi-1; aging; homeostasis; p16Ink4a; stem/progenitor cells; submandibular gland
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