RGC-32 and diseases: the first 20 years

Vlaicu, Sonia I.; Tatomir, Alexandru; Anselmo, Freidrich; Boodhoo, Dallas; Chira, Romeo; Rus, Violeta; Rus, Horea

doi:10.1007/s12026-019-09080-0

Cited by 12 publications

(14 citation statements)

References 74 publications

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“…Subsequent studies have shown that RGC-32 is an important cell cycle regulator, driving cell cycle progression in a number of cell types, such as smooth muscle cells and endothelial cells, by promoting the activity of CDC2/cyclin B complexes and Akt kinase (2,3). RGC-32 has also been shown to be involved in cell differentiation, tumorigenesis, and wound healing (4,5). Furthermore, RGC-32 has been found to be crucial for the TGFb-induced epithelial-to-mesenchymal transition in renal fibrosis and cancer metastasis (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis

et al. 2021

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Astrocytes are increasingly recognized as critical contributors to multiple sclerosis pathogenesis. We have previously shown that lack of Response Gene to Complement 32 (RGC-32) alters astrocyte morphology in the spinal cord at the peak of experimental autoimmune encephalomyelitis (EAE), suggesting a role for RGC-32 in astrocyte differentiation. In this study, we analyzed the expression and distribution of astrocytes and astrocyte progenitors by immunohistochemistry in spinal cords of wild-type (WT) and RGC-32-knockout (KO) mice with EAE and of normal adult mice. Our analysis showed that during acute EAE, WT astrocytes had a reactive morphology and increased GFAP expression, whereas RGC-32 KO astrocytes had a morphology similar to that of radial glia and an increased expression of progenitor markers such as vimentin and fatty acid binding protein 7 (FABP7). In control mice, GFAP expression and astrocyte density were also significantly higher in the WT group, whereas the number of vimentin and FABP7-positive radial glia was significantly higher in the RGC-32 KO group. In vitro studies on cultured neonatal astrocytes from WT and RGC-32 KO mice showed that RGC-32 regulates a complex array of molecular networks pertaining to signal transduction, growth factor expression and secretion, and extracellular matrix (ECM) remodeling. Among the most differentially expressed factors were insulin-like growth factor 1 (IGF1), insulin-like growth factor binding proteins (IGFBPs), and connective tissue growth factor (CTGF); their expression was downregulated in RGC-32-depleted astrocytes. The nuclear translocation of STAT3, a transcription factor critical for astrogliogenesis and driving glial scar formation, was also impaired after RGC-32 silencing. Taken together, these data suggest that RGC-32 is an important regulator of astrocyte differentiation during EAE and that in the absence of RGC-32, astrocytes are unable to fully mature and become reactive astrocytes.

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Section: Introductionmentioning

confidence: 99%

RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis

et al. 2021

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“…Table 1 shows differentially regulated candidates (0.8 > FC > 1.2), of which increased phosphorylation of the PI3K-kinase p85-subunit alpha/gamma had most relevance to RGCC signaling. PI3K p85 phosphorylation links the Class I PI3K pathway to Akt [ 32 ] which controls RGCC [ 33 ]. The role of Akt was verified by siRNA which showed that knockdown of Akt1/2 or Akt1 alone prevented an increase in P .…”

Section: Resultsmentioning

confidence: 99%

“…gingivalis . RGCC regulates cell cycle progression along with cell differentiation and fibrosis [ 33 ]. RGCC is highly expressed in a number of tumors [ 60 ] and can promote tumor cell proliferation and EMT [ 61 ], although the functionality of RGCC can be cell and context specific [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interrogation of our RNA-Seq database, along with corroboration by siRNA suppression, identified RGCC as involved in this property of P. gingivalis. RGCC regulates cell cycle progression along with cell differentiation and fibrosis [33]. RGCC is highly expressed in a…”

Section: Plos Pathogensmentioning

confidence: 99%

“…Our data suggest that RGCC occupies a signaling hub in the manipulation of the host cell by P. gingivalis through the Ltp1 phosphatase (shown schematically in Fig 10). A phosphoprotein antibody array analysis of TIGK cells expressing ectopic Ltp1 indicated an increase in the activity of PI3K which is upstream of Akt, a regulator of RGCC [33,66]. Immunoblotting showed that in TIGKs infected with a Ltp1-deficient mutant there was a decrease in S473 phosphorylation, which is required for full Akt activity, and siRNA suppression of AKT prevented an increase in RGCC transcription in response to P. gingivalis.…”

Section: Plos Pathogensmentioning

confidence: 99%

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A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC

et al. 2021

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Tyrosine phosphatases are often weaponized by bacteria colonizing mucosal barriers to manipulate host cell signal transduction pathways. Porphyromonas gingivalis is a periodontal pathogen and emerging oncopathogen which interferes with gingival epithelial cell proliferation and migration, and induces a partial epithelial mesenchymal transition. P. gingivalis produces two tyrosine phosphatases, and we show here that the low molecular weight tyrosine phosphatase, Ltp1, is secreted within gingival epithelial cells and translocates to the nucleus. An ltp1 mutant of P. gingivalis showed a diminished ability to induce epithelial cell migration and proliferation. Ltp1 was also required for the transcriptional upregulation of Regulator of Growth and Cell Cycle (RGCC), one of the most differentially expressed genes in epithelial cells resulting from P. gingivalis infection. A phosphoarray and siRNA showed that P. gingivalis controlled RGCC expression through Akt, which was activated by phosphorylation on S473. Akt activation is opposed by PTEN, and P. gingivalis decreased the amount of PTEN in epithelial cells. Ectopically expressed Ltp1 bound to PTEN, and reduced phosphorylation of PTEN at Y336 which controls proteasomal degradation. Ltp-1 induced loss of PTEN stability was prevented by chemical inhibition of the proteosome. Knockdown of RGCC suppressed upregulation of Zeb2 and mesenchymal markers by P. gingivalis. RGCC inhibition was also accompanied by a reduction in production of the proinflammatory cytokine IL-6 in response to P. gingivalis. Elevated IL-6 levels can contribute to periodontal destruction, and the ltp1 mutant of P. gingivalis incited less bone loss compared to the parental strain in a murine model of periodontal disease. These results show that P. gingivalis can deliver Ltp1 within gingival epithelial cells, and establish PTEN as the target for Ltp1 phosphatase activity. Disruption of the Akt1/RGCC signaling axis by Ltp1 facilitates P. gingivalis-induced increases in epithelial cell migration, proliferation, EMT and inflammatory cytokine production.

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The role of Map1b in regulating osteoblast polarity, proliferation, differentiation and migration

Peng,

Zhang,

et al. 2024

Bone

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RGC-32 and diseases: the first 20 years

Cited by 12 publications

References 74 publications

RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis

RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis

A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC

The role of Map1b in regulating osteoblast polarity, proliferation, differentiation and migration

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