PERK is essential for neonatal skeletal development to regulate osteoblast biology. Jianwen Wei

ISBN: 9780549902447

Published:

NOOKstudy eTextbook

130 pages


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PERK is essential for neonatal skeletal development to regulate osteoblast biology.  by  Jianwen Wei

PERK is essential for neonatal skeletal development to regulate osteoblast biology. by Jianwen Wei
| NOOKstudy eTextbook | PDF, EPUB, FB2, DjVu, AUDIO, mp3, ZIP | 130 pages | ISBN: 9780549902447 | 7.15 Mb

PERK (eukaryotic translation initiation factor 2 alpha kinase 3) is an endoplasmic reticulum (ER) resident transmembrane protein. In response to alterations of ER homeostasis, PERK is activated to modulate specific mRNA translational upregulation asMorePERK (eukaryotic translation initiation factor 2 alpha kinase 3) is an endoplasmic reticulum (ER) resident transmembrane protein. In response to alterations of ER homeostasis, PERK is activated to modulate specific mRNA translational upregulation as well as transient repression of global protein synthesis through phosphorylating eIF2alpha at serine 51.

Loss-function mutations of PERK in humans and mice cause severe neonatal development defects, including diabetes, growth retardation, exocrine pancreatic atrophy and multiple skeletal dysplasias.-To investigate the physiological functions of PERK in regulation of mammalian skeletal development, comprehensive analyses were carried out on tissue, cellular and molecular levels in PERK-deficient mice and Perk-/- osteoblasts. Neonatal Perk-/- mice are severely osteopenic, which is in part caused by multiple defects in osteoblasts (bone forming cells), including a deficiency in the number of mature osteoblasts, impaired osteoblast differentiation, and reduced secretion of type I collagen.

Further studies showed that compromised osteoblast differentiation and maturation in the absence of PERK is associated with decreased expression of Runx2 and Osterix, two key regulators of osteoblast development. Besides the differentiation defect, the low osteoblast mass phenotype in Perk-/- mice is also caused by reduced osteoblast proliferation. Perk-/- osteoblasts exhibit slow cell cycle progression along with reduced expression of key cell cycle factors including cyclin D, cyclin E, cyclin A, Cdc2, and CDK2. In addition, abnormal retention of procollagen I within the endoplasmic reticulum and reduced mature collagen production are manifested in Perk-/- osteoblasts.

The imperfect collagen biosynthesis in Perk-/- osteoblasts is coincident with compromised ATF6 and IRE1/XBP1 UPR pathways. Normal osteoblast viability, normal global protein synthesis, low procollagen synthesis rate and no upregulation of ER stress markers are observed in Perk-/- osteoblasts, suggesting that the osteoblast defects are not due to persistent activation of the classical unfolded protein response.

In addition, normal expression and activity of ATF4 seen in Perk-/- osteoblasts, together with its distinct role in controlling collagen synthesis, suggests that ATF4 is not a major target of PERK in regulation of osteoblast biology.



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