SomaticApc mutations are selected upon their capacity to inactivate the ?-catenin downregulating activity

Smits, Ron; Hofland, Nandy; Edelmann, Winfried; Geugien, Marjan; Jagmohan–Changur, Shantie; Albuquerque, Cristina; Breukel, Cor; Kucherlapati, Raju; Kielman, Menno F.; Fodde, Riccardo

doi:10.1002/1098-2264(2000)9999:9999<::aid-gcc1033>3.0.co;2-r

Cited by 87 publications

(78 citation statements)

References 32 publications

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“…Western blotting was performed as described (15). Primary antibodies used include mouse-anti-␤-catenin (BD Transduction Laboratories), diluted 1:1000; mouse anti-human IgG (Fc␥ fragment-specific), diluted 1:1000 (Jackson ImmunoResearch Laboratories Inc., West Grove, PA); rabbit anti-P73-c-Jun, diluted 1:1000 (Cell Signaling Technology, Beverly, MA); rabbit anti-c-Jun, diluted 1:1000 (H79; Santa Cruz Biotechnology, Inc., Santa Cruz, CA); rabbit anti-phospho-ATF2, diluted 1:1000 (Thr 71 ; Cell Signaling Technology); rabbit anti-ATF2, diluted 1:1000 (C19; Santa Cruz Biotechnology); rabbit anti-c-Fos, diluted 1:1000 (06-431, Upstate, Charlottesville, VA); and rabbit anti-MSH2, diluted 1:15,000 (22). Primary antibodies were detected using sheep anti-mouse horseradish peroxidase conjugate, diluted 1:10,000 (Amersham Biosciences) or goat anti-rabbit-horseradish peroxidase, diluted 1:10,000 (Jackson ImmunoResearch Laboratories).…”

Section: Methodsmentioning

confidence: 99%

Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected

Bent

Huls

et al. 2004

Journal of Biological Chemistry

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Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, ␤-catenin and T-cell factor/lymphoid-enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.Progressive development of fluid-filled cysts in autosomal dominant polycystic kidney disease (ADPKD) 1 results in chronic renal failure. In the majority of patients, the disease can be accounted for by a mutation in the PKD1 gene (1, 2), whereas a minority suffers from a mutation in the PKD2 gene (3, 4). The precise function of polycystin-1 and polycystin-2, the proteins encoded by the PKD1 and PKD2 gene, respectively, remains to be elucidated. Polycystin-1 is predicted to be a transmembrane protein of ϳ460 kDa. The large extracellular N terminus contains multiple domains thought to be involved in cell-cell and cell-matrix interactions. The intracellular C terminus of polycystin-1 contains putative phosphorylation sites and a coiled-coil domain that can mediate protein-protein interactions.Several studies have implicated a role for polycystin-1 in signal transduction. Overexpression of the C-terminal region of polycystin-1 in human embryonic kidney 293T (HEK293T) cells has been shown to activate the Wnt signaling pathway (5) and the activator protein-1 (AP-1) transcription factor complex (6, 7). Furthermore, overexpression of a full-length polycystin-1 construct has been reported to activate the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway (8). These signaling pathways are all involved in key cellular processes such as proliferation and differentiation, cell cycle regulation, and cell survival. Since these cellular processes are essential for normal function, the signaling pathways governing them are tightly regulated. We ...

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Section: Methodsmentioning

confidence: 99%

Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected

Bent

Huls

et al. 2004

Journal of Biological Chemistry

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“…Instead, the 'two hits' are coselected to leave a critical, yet partial, ability to down-regulate β-catenin and hence lower the level of Wnt signalling. The explanation for these observations probably lies in the fact that too high a level of Wnt signalling is sub-optimal for tumourigenesis [2][3][4]. Indeed, different regions of the bowel have different optimal levels of Wnt for tumour growth.…”

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confidence: 99%

CDC4/FBXW7 and the ‘just enough’ model of tumourigenesis

Belnoue-Davis

Tomlinson

2012

The Journal of Pathology

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There is good evidence to show that cancer-causing mutations are not always simple gain-and loss-of-function changes. One example is the APC gene, where the combination of mutations produces a 'just-right' level of Wnt signalling. A recent article by Berger and colleagues posited a 'continuum model' in which increasing or decreasing gene expression of function was linearly associated with tumourigenesis. Berger also proposed an 'obligate haploinsufficiency' or 'failsafe' model, whereby heterozygous mutations produce sufficient derangement for tumourigenesis, yet homozygous mutations are cell-lethal or senescence-causing. One gene highlighted by Berger and colleagues as an example of a gene following a 'continuum' or 'fail-safe' model was FBXW7/ CDC4, a gene mutated in several different types of malignancy. We have analysed the COSMIC FBXW7 data. FBXW7 does not obviously follow a 'continuum' or 'fail-safe' model and the most common mutant genotypes are mono-allelic missense changes that affect critical arginine residues involved in interactions with substrates. There is no strong selection for complete loss of FBXW7 protein function, but bi-allelic inactivating mutations do occur. For FBXW7, we suggest a variant of 'just right' which we call 'just enough'. For FBXW7 mutations that occur away from the propellor tips, the heterozygote may have some effect on tumourigenesis, but there is selective pressure for a 'second hit'. For propellor tip mutations, by contrast, there is weak pressure for a 'second hit' because they usually provide sufficient functional derangement on their own. Keywords continuum model; just right model; just enough model; two hits; FBXW7/CDC4The identification of mutant genes that drive tumourigenesis has relied on two factors: an observed mutation frequency above background and an ability to assign a strong effect on protein function. For most of the established cancer genes in human tumours, mutations either inactivate protein function in the fashion of a classic tumour suppressor or activate oncogene function by mutation of specific amino acids or by another mechanism, such as translocation or copy number change. Thus, whilst not all mutations of a gene necessarily have identical effects, all VHL mutations are thought to inactivate the protein and all KRAS, NRAS, and BRAF mutations cause constitutive activity. (Figure 1).We have previously suggested that the 'just right' model might also apply more generally in tumourigenesis, less in terms of the spectra of mutations in individual genes, and more as an explanation for why specific cancer types tend to acquire mutations in specific genes, sometimes within the same signalling pathways [6]. Thus, we hypothesize that APC may be unusual, in that different mutant alleles can have optimal or suboptimal effects, but the 'just right' principle may hold more widely.A recent article by Berger et al [7] focused on the interesting topic of the importance of gene dosage changes in promoting tumourigenesis. In summary, the authors highlighted t...

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“…Firstly, wildtype as well as Msh2 +/7 and Msh2 7/7 primary mouse dermal ®bro-blasts (MDFs) derived from newborn mice with a deletion in Msh2 exon 7 (Smits et al, 2000) were isolated. Furthermore, adenovirus E1A immortalized wildtype and Msh2 7/7 MEFs (Berry et al, 2000) derived from embryos with a hygromycin insertion between codons 588 and 589 of Msh2 (de Wind et al, 1995) were used.…”

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confidence: 99%

“…Figure 1 Expression of Msh2 protein in wildtype and Msh2 7/7 mouse cells. Cell lysates from E14 (129/Ola) derived ES cell line IB10.51 (de Wind et al, 1999), adenovirus E1A immortalized wildtype and Msh2 7/7 MEFs (Berry et al, 2000) derived from wildtype and Msh2 7/7 mouse embryos (de Wind et al, 1995), and primary wildtype, Msh2 +/7 and Msh2 7/7 MDFs (derived from Msh2 D7N newborn mice; Smits et al, 2000) were prepared in Laemmli bu er. The lysates were subjected to Western blotting analysis using a rabbit polyclonal antibody raised against fulllength mouse Msh2 protein (de Wind et al, 1998).…”

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confidence: 99%

“…The upper band represents an aspeci®c signal of the used antibody and serves as control for equal protein loading Figure 2 Repair of CPD in primary mouse dermal ®broblasts. Representative autoradiograms (a) and graphs (b and c) showing the removal of CPD from the transcribed strand (TS) and nontranscribed strand (NTS) of the active p53 and Hprt genes in primary MDFs derived from wildtype and Msh2 7/7 newborn mice (Smits et al, 2000) irradiated with 10 J/m 2 UV. CPD frequencies in the 16 kb EcoRI restriction fragment of the p53 gene and the 18 kb EcoRI restriction fragment containing exon 6 ± 9 of the Hprt gene were measured as described previously (Van Ho en et al, 1995;Van Sloun et al, 1999).…”

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Mouse mismatch repair gene Msh2 is not essential for transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers

et al. 2001

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The human mutS homolog gene MSH2 is essential for DNA mismatch repair (MMR) and defects in this gene can result in increased mutagenesis, genomic instability and hereditary nonpolyposis colorectal cancer (HNPCC). Besides correcting mismatch errors arising from DNA replication, it was shown that de®ciencies in bacterial and human MMR genes including MSH2 resulted in defective transcription-coupled repair (TCR) of UV-induced photolesions. Here we show that MMRde®cient ®broblasts derived from two independent isogenic mouse strains with de®ned Msh2 de®ciencies are as pro®cient in TCR of UV-induced cyclobutane pyrimidine dimers (CPD) as wildtype ®broblasts. Our results indicate that in mouse cells Msh2 is not essential for TCR of UV-induced CPD in contrast to bacteria and human cells and suggest that the biological e ects of UV in mouse Msh2 7/7 cells and mice are not due to defective TCR. Oncogene (2001) 20, 538 ± 541.

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SomaticApc mutations are selected upon their capacity to inactivate the ?-catenin downregulating activity

Cited by 87 publications

References 32 publications

Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected

Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected

CDC4/FBXW7 and the ‘just enough’ model of tumourigenesis

Mouse mismatch repair gene Msh2 is not essential for transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers

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