Disruption of the <i>Fbxw8</i> Gene Results in Pre- and Postnatal Growth Retardation in Mice

Tsutsumi, Takeshi; Kuwabara, Hiroshi; Arai, Takehiro; Xiao, Yonghong; DeCaprio, James A.

doi:10.1128/mcb.01665-07

Cited by 47 publications

(52 citation statements)

References 36 publications

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“…In addition to possible GH/IGF resistance, dysregulation of IGFBP2 and IGFBP5 had previously been identified (Huber et al 2010) with downregulation of IGFBP2 and upregulation of IGFBP5 expression seen in fibroblasts from two patients with OBSL1 mutations. By contrast, upregulation of IGFBP2 is seen in the Cul7 K/K mouse (Tsutsumi et al 2008). We now demonstrate that regardless of mutation status, all 3-M cell lines show reduced secreted protein levels of IGFBP2 and -7.…”

Section: Discussionmentioning

confidence: 98%

“…In clinical reports, there are little, if any, data on the status of the GH-IGF axis in 3-M patients, nor are there data on the degree of height restriction by mutation type. We do, however, know that IGFBP gene expression is abnormal in cells derived from 3-M patients (Huber et al 2010) and in the Cul7 K/K mouse (Tsutsumi et al 2008). This study has addressed the following: i) identification and frequency of mutations in the three genes in those with a clinical diagnosis of 3-M; ii) height at presentation, the status of the GH-IGF axis as measured in serum assays by mutation status and IGFBP generation from cultured cell lines; and iii) in view of the relative clinical resistance to GH treatment and involvement of IRS1, MAPK and AKT, an assessment of the activation of signalling pathways by GH and IGF1.…”

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confidence: 99%

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Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Hanson¹,

Murray²,

Coulson³

et al. 2012

Journal of Molecular Endocrinology

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3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Hanson¹,

Murray²,

Coulson³

et al. 2012

Journal of Molecular Endocrinology

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“…Fbxw8 –/– mice have a reduced placental size but appear to have no isolated placental abnormalities. Tsutsumi et al [33] confirmed the Fbxw8 –/– phenotype and underlined the similarities between Fbxw8 –/– and Cul7 –/– mice. Growth restriction of Fbxw8 –/– mice continued postnatally, but the mice were otherwise normal.…”

Section: Cul7 and The Ubiquitin-proteasome Pathwaymentioning

confidence: 50%

“…Growth restriction of Fbxw8 –/– mice continued postnatally, but the mice were otherwise normal. Arai et al [31] established that Fbxw8 protein levels were reduced in Cul7 –/– cells, with Tsutsumi et al [33] demonstrating that Cul7 levels were also reduced in Fbxw8 –/– mouse embryonic fibroblast (MEF) cells. Fbxw8 –/– MEFs grew very poorly when compared to Fbxw8 +/– or Fbxw8 +/+ MEFs.…”

Section: Cul7 and The Ubiquitin-proteasome Pathwaymentioning

confidence: 99%

The Genetics of 3-M Syndrome: Unravelling a Potential New Regulatory Growth Pathway

Hanson¹,

Murray²,

Black

et al. 2011

Horm Res Paediatr

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3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth.

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“…The 26S proteasome, which regulates the proteolytic activity of the matrix metalloproteinases (MMPs)-2 and -9, is required during implantation process (Wang et al 2004). The important function of other ubiquitination-related proteins such as the Ub-conjugating enzyme UBCM4 (Harbers et al 1996), the proteasome activator PSME3 (PA28g; Murata et al 1999), Ub ligase CUL7 (Huber et al 2005) and FBXW8 (Tsutsumi et al 2008) was demonstrated by the phenotype of mouse models with placenta and intrauterine embryonic growth retardation. The Smurf2 gene, encoding E3 class protein, is involved in trophoblast cell invasion and embryo implantation (Yang et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Embryo implantation failure and other reproductive defects in Ube2q1-deficient female mice

et al. 2013

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The ubiquitination process is indispensable for proteome regulation. Three classes of ubiquitin (Ub)-related proteins can be distinguished: E1, E2 and E3. Proteins from the E2 class are responsible for the transfer of Ubls from E1 to the target protein. For this activity, interaction with class E3 ligases is usually required. Ub-conjugating enzyme E2Q 1 (UBE2Q1) belongs to the E2 class of Ub-related enzymes and is demonstrated to be involved in the regulation of membrane B4GALT1 protein. Here, we demonstrate that human UBE2Q1 and mouse Ube2q1 are widely expressed and highly conserved genes. To elucidate the function of UBE2Q1 protein, we generated knockout mouse model. No overt phenotype was detected in UBE2Q1-deficient males, but in mutant females, pleiotropic reproductive defects were observed including altered oestrus cycle, abnormal sexual behaviour and reduced offspring care. Moreover, in the uterus of mutant females, significantly increased embryonic lethality and decreased implantation capacity of homozygous mutant embryos were noticed. We found that Ube2q1 is not expressed in the uterus of non-pregnant females but its expression is up-regulated during pregnancy. Taken together, Ube2q1 is involved in different aspects of female fertility.

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Disruption of the Fbxw8 Gene Results in Pre- and Postnatal Growth Retardation in Mice

Cited by 47 publications

References 36 publications

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

The Genetics of 3-M Syndrome: Unravelling a Potential New Regulatory Growth Pathway

Embryo implantation failure and other reproductive defects in Ube2q1-deficient female mice

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