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Cathleen Wallmuth, Na Luo, Xinyao Hu, Clark Wells, Yang Sun; The Role of Inositol Polyphosphate 5-Phosphatases INPP5B and OCRL in Cell Cycle Progression: Implications for Oculocerebrorenal Syndrome of Lowe. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4224.
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© ARVO (1962-2015); The Authors (2016-present)
Oculocerebrorenal syndrome of Lowe (Lowe syndrome) is an X-linked disorder characterized by congenital glaucoma and cataracts, brain abnormalities, and renal dysfunction. It is caused by mutations in the OCRL gene, which encodes for an inositol polyphosphate 5-phosphatase. Phosphoinositides have been shown to play a critical role during abscission in cytokinesis, dysfunction of which results in cell division defects. Because the potential functions of OCRL during cell division are currently unknown, this study investigated the role of OCRL, and its paralog, INPP5B, in this process. The findings presented will contribute to our understanding of the underlying mechanisms that contribute to the development of Lowe syndrome.
Initially, the intracellular localization of OCRL and INPP5B was determined in cells undergoing different stages in the cell cycle. For this purpose, we performed double thymidine block in hTERT-immortalized retinal pigmented epithelial (RPE1) and fibroblast cells to arrest cell cycle progression. Serum addition allowed their re-initiation of cell cycling and fixation of the cells was performed at 0, 6, 8, 10, 12 hours. To visualize the intracellular localization of OCRL and INPP5B, cells were immunostained for OCRL or INPP5B, and either the nucleus (stained with DAPI), cytokinesis bridges (immunostained with acetylated alpha-tubulin), the midbody (immunostained with Rab35) or centrioles (immunostained with gamma-tubulin and the Aurora B kinase). We then examined either cells silenced for OCRL expression or Lowe syndrome patient cells for defects in cell cycle progression.
These experiments revealed that OCRL accumulates along the nuclear membrane during early prophase, but translocates into the nucleus during prophase. Similar to OCRL, INPP5B was found to translocate to the nucleus during nuclear membrane breakdown and appears to surround the chromatin during cell cycle progression. Consistent with OCRL having a required role in these processes, Lowe patient cells exhibit slower cell cycle progression and knockdown of OCR affects the normal cell cycle progression.
In conclusion, the nuclear distribution of both OCRL and INPP5B suggests that these inositol polyphosphate 5-phosphatases may play a role in cell cycle progression.
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