CBX7

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Chromobox protein homolog 7

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Biological functions of chromobox (CBX) proteins in stem cell self-renewal, lineage-commitment, cancer and development.

Epigenetic regulatory proteins support mammalian development, cancer, aging and tissue repair by controlling many cellular processes including stem cell self-renewal, lineage-commitment and senescence in both skeletal and non-skeletal tissues. We review here our knowledge of epigenetic regulatory protein complexes that support the formation of inaccessible heterochromatin and suppress expression of cell and tissue-type specific biomarkers during development. Maintenance and formation of heterochromatin critically depends on epigenetic regulators that recognize histone 3 lysine trimethylation at residues K9 and K27 (respectively, H3K9me3 and H3K27me3), which represent transcriptionally suppressive epigenetic marks. Three chromobox proteins (i.e., CBX1, CBX3 or CBX5) associated with the heterochromatin protein 1 (HP1) complex are methyl readers that interpret H3K9me3 marks which are mediated by H3K9 methyltransferases (i.e., SUV39H1 or SUV39H2). Other chromobox proteins (i.e., CBX2, CBX4, CBX6, CBX7 and CBX8) recognize H3K27me3, which is deposited by Polycomb Repressive Complex 2 (PRC2; a complex containing SUZ12, EED, RBAP46/48 and the methyl transferases EZH1 or EZH2). This second set of CBX proteins resides in PRC1, which has many subunits including other polycomb group factors (PCGF1, PCGF2, PCGF3, PCGF4, PCGF5, PCGF6), human polyhomeotic homologs (HPH1, HPH2, HPH3) and E3-ubiquitin ligases (RING1 or RING2). The latter enzymes catalyze the subsequent mono-ubiquitination of lysine 119 in H2A (H2AK119ub). We discuss biological, cellular and molecular functions of CBX proteins and their physiological and pathological activities in non-skeletal cells and tissues in anticipation of new discoveries on novel roles for CBX proteins in bone formation and skeletal development.


Keywords

  • Aging
  • Bone
  • CBX1
  • CBX2
  • CBX3
  • CBX4
  • CBX5
  • CBX6
  • CBX7
  • CBX8
  • Cancer
  • Chromatin
  • Development
  • Epigenetics
  • H3K27me3
  • H3K9me3
  • Lineage-commitment
  • Osteoblast
  • Senescence
  • Stem cell


Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway.

Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3) is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β) pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS) through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS), independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP) without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

MeSH Terms

  • Aged, 80 and over
  • Aging
  • Animals
  • Cell Line
  • Cells, Cultured
  • Cellular Senescence
  • Child
  • Cyclin-Dependent Kinase Inhibitor p21
  • Extracellular Matrix
  • Fibroblasts
  • Humans
  • Integrin beta3
  • Isotope Labeling
  • Mice
  • Polycomb Repressive Complex 1
  • Protein Subunits
  • RNA, Messenger
  • Signal Transduction
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Up-Regulation

Keywords

  • CBX7
  • ITGB3
  • Palbociclib
  • SASP
  • TGFβ
  • aging
  • cilengitide
  • integrin
  • senescence
  • β3


CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a).

Polycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR-9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR-9-1 and miR-9-2 as part of a regulatory negative feedback loop. The miR-9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin-dependent kinase inhibitor (CDKI) p16(INK4a) during senescence. The ability of the miR-9 family to regulate senescence could have implications for understanding the role of miR-9 in cancer and aging.

MeSH Terms

  • Aging
  • Cell Differentiation
  • Cell Line
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16
  • Down-Regulation
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • MicroRNAs
  • Polycomb Repressive Complex 1

Keywords

  • CBX7
  • Polycomb
  • miR-9
  • p16INK4a
  • senescence