Dataset Information

Sexually dimorphic leanness and hypermobility in p16^Ink4a/CDKN2A-deficient mice coincides with phenotypic changes in the cerebellum.

ABSTRACT: p16^Ink4a/CDKN2A is a tumor suppressor that critically regulates the cell cycle. Indeed, p16^Ink4a deficiency promotes tumor formation in various tissues. We now report that p16^Ink4a deficiency in female mice, but not male mice, induces leanness especially in old age, as indicated by lower body weight and smaller white adipose tissue, although other major organs are unaffected. Unexpectedly, the integrity, number, and sizes of adipocytes in white adipose tissue were unaffected, as was macrophage infiltration. Hence, hypermobility appeared to be accountable for the phenotype, since food consumption was not altered. Histological analysis of the cerebellum and deep cerebellar nuclei, a vital sensorimotor control center, revealed increased proliferation of neuronal cells and improved cerebellum integrity. Expression of estrogen receptor β (ERβ) and PCNA also increased in deep cerebellar nuclei, implying crosstalk between p16^Ink4a and ERβ. Furthermore, p16^Ink4a deficiency expands LC3B⁺ cells and GFAP⁺ astrocytes in response to estrogen. Collectively, the data suggest that loss of p16^INK4a induces sexually dimorphic leanness in female mice, which appears to be due to protection against cerebellar senescence by promoting neuronal proliferation and homeostasis via ERβ.

SUBMITTER: Kim KH

PROVIDER: S-EPMC6671985 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sexually dimorphic leanness and hypermobility in p16Ink4a/CDKN2A-deficient mice coincides with phenotypic changes in the cerebellum.

Kim Kwang H KH Cho Yejin Y Lee Jaehoon J Jeong Haengdueng H Lee Yura Y Kim Soo In SI Kim Chang-Hoon CH Lee Han-Woong HW Nam Ki Taek KT

Scientific reports 20190801 1

p16Ink4a/CDKN2A is a tumor suppressor that critically regulates the cell cycle. Indeed, p16Ink4a deficiency promotes tumor formation in various tissues. We now report that p16Ink4a deficiency in female mice, but not male mice, induces leanness especially in old age, as indicated by lower body weight and smaller white adipose tissue, although other major organs are unaffected. Unexpectedly, the integrity, number, and sizes of adipocytes in white adipose tissue wer ...[more]

PMID: 31371816

Similar Datasets

Project description:Background & aimsOncogenic mutations in KRAS, coupled with inactivation of p53, CDKN2A/p16INK4A, and SMAD4, drive progression of pancreatic ductal adenocarcinoma (PDA). Overexpression of MYC and deregulation of retinoblastoma (RB) further promote cell proliferation and make identifying a means to therapeutically alter cell-cycle control pathways in PDA a significant challenge. We previously showed that the basic helix-loop-helix transcription factor E47 induced stable growth arrest in PDA cells in vitro and in vivo. Here, we identified molecular mechanisms that underlie E47-induced growth arrest in low-passage, patient-derived primary and established PDA cell lines.MethodsRNA sequencing was used to profile E47-dependent transcriptomes in 5 PDA cell lines. Gene Ontology analysis identified cell-cycle control as the most altered pathway. Small interfering RNA/short hairpin RNA knockdown, small-molecule inhibitors, and viral expression were used to examine the function of E47-dependent genes in cell-cycle arrest. Cell morphology, expression of molecular markers, and senescence-associated β-galactosidase activity assays identified cellular senescence.ResultsE47 uniformly inhibited PDA cell-cycle progression by decreasing expression of MYC, increasing the level of CDKN1B/p27KIP1, and restoring RB tumor-suppressor function. The molecular mechanisms by which E47 elicited these changes included altering both RNA transcript levels and protein stability of MYC and CDKN1B/p27KIP1. At the cellular level, E47 elicited a senescence-like phenotype characterized by increased senescence-associated β-galactosidase activity and altered expression of senescence markers.ConclusionsE47 governs a highly conserved network of cell-cycle control genes, including MYC, CDKN1B/p27KIP1, and RB, which can induce a senescence-like program in PDA cells that lack CDKN2A/p16INK4A and wild-type p53. RNA sequencing data are available at the National Center for Biotechnology Information GEO at https://www.ncbi.nlm.nih.gov/geo/; accession number: GSE100327.

Dataset Information

Sexually dimorphic leanness and hypermobility in p16^Ink4a/CDKN2A-deficient mice coincides with phenotypic changes in the cerebellum.

Publications

Sexually dimorphic leanness and hypermobility in p16<sup>Ink4a</sup>/CDKN2A-deficient mice coincides with phenotypic changes in the cerebellum.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets