Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers

Jung, Barbara; Doctolero, Ryan T.; Tajima, Akihiro; K., Nguyen, Alexie; Keku, Temitope O.; Sandler, Robert S.; Carethers, John M.

doi:10.1053/j.gastro.2004.01.008

Cited by 123 publications

(138 citation statements)

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“…We demonstrated a similarly high mutational rate in primary colon cancer specimens, accompanied by loss of ACVR2 protein expression in the majority of colon cancers. 2 Our primary human tumor data underscore the potential importance of activin signaling in colon cancer. To date, little is known about the mechanisms and cellular effects of activin signaling in colon cancer.…”

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confidence: 77%

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Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

et al. 2007

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Background & Aims-Colon cancers with high-frequency microsatellite instability (MSI-H) develop frameshift mutations in tumor suppressors as part of their pathogenesis. ACVR2 is mutated at its exon 10 polyadenine tract in >80% of MSI-H colon cancers, coinciding with loss of protein. ACVR2 transmits the growth effects of activin via phosphorylation of SMAD proteins to affect gene transcription. The functional effect of activin in colon cancers has not been studied. We developed and characterized a cell model in which we studied how activin signaling affects growth.

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confidence: 77%

“…1 More recently, ACVR2 was shown to be mutated in the majority of high-frequency microsatellite instability (MSI-H) colon cancers, with loss of protein expression. 2 However, the functional consequences of loss of activin signaling in MSI-H colon cancer are unknown.…”

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confidence: 99%

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

et al. 2007

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“…The most frequently mutated MSI CRC target gene is TGFBR2 with a mutation frequency up to 90% (20)(21)(22). Genes with similar mutation frequency to that observed in MYH11 are ACVRII (58-83%), BAX (37-64%), MSH3 (26-55%), and CASP5 (48-66%) (20,21,(23)(24)(25)(26); to our knowledge, the latter four have not been shown to be mutated in MSS CRC. Thus, the genetic, functional, and animal model-derived evidence linking MYH11 to intestinal neoplasia is comparable with or superior to established MSI target genes.…”

Section: Discussionmentioning

confidence: 99%

Unregulated smooth-muscle myosin in human intestinal neoplasia

Alhopuro¹,

Phichith

Tuupanen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.colorectal cancer ͉ microsatellite instability ͉ Peutz-Jeghers syndrome ͉ smmhc/myh11 G ermline mutations in human myosin heavy chain genes contribute to multiple inherited human diseases (1). In addition, smooth-muscle myosin (MYH11) participates in formation of an oncogenic fusion gene CBFB/MYH11 in acute myeloid leukaemia (2).Microsatellite instability (MSI) occurs in Ϸ15% of colorectal cancers (CRC), and is a consequence of defects in the DNA mismatch repair (MMR) system (3). Mutations occurring during DNA replication are not repaired, resulting in genetic instability that particularly affects short repetitive DNA sequences. Mutations that result in malignant progression are selected and thus detected in surgically removed MSI cancers. Passenger mutations also occur frequently in this mutator tumor type (4-6).By examining gene expression data (7), we had identified MYH11 as a gene with reduced expression in MSI CRCs compared with normal colon samples. The reduced expression of MYH11 in CRCs could simply reflect a larger smooth-muscle component in our normal colon specimens. Nevertheless, the differential expression prompted us to examine whether MYH11 has a mononucleotide tract in the coding sequence, because mononucleotide tracts are prone to mutations under MSI. Two splice variants, SM1 and SM2, which are distinct in the Cterminal tailpiece, are produced from the MYH11 gene. Indeed, the SM2 isoform of MYH11 was observed to harbor a mononucleotide repeat of 8 cytosines (C8). Thus, MYH11 was identified as a candidate MSI colon cancer gene. Dominant-negative germ-line mutations in MYH11 occur in a syndrome predisposing to thoracic aortic aneurysm/aortic dissection (TAAD) and patent ductus arteriosus (8). The TAAD phenotype closely resembles the on...

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“…Among colorectal cancers, key receptors for TGFβ and activin signaling are often mutated, muting SMAD signaling and subsequent growth suppression [30][31][32]. We have previously shown intact BMP signaling in primary colon cancers and cell lines [5], suggesting that if BMP growth suppression was important for growth control, other mechanisms for inhibiting BMP-induced growth suppression in addition to receptor or SMAD4 mutation seen with the familial JP syndrome may be operative.…”

Section: Discussionmentioning

confidence: 99%

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Beck

Jung

Rosario

et al. 2007

Cellular Signalling

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Bone morphogenetic proteins (BMPs) regulate cell differentiation, proliferation, and apoptosis through a canonical SMAD signaling cascade. Absence of BMP signaling causes the formation of intestinal juvenile polyps in the colon cancer-prone syndrome familial juvenile polyposis. As sporadic colon cancers appear to have intact BMP signaling, we evaluated if K-RAS, driving a mitogenic pathway frequently activated in colon cancer, negatively affects BMP growth suppression. We treated non-tumorigenic but activated RAS/ERK FET cells with BMP2, and in combination with pharmacological or genetic inhibition of RAS/ERK, examined BMP-SMAD signaling, transcriptional activity, and cell growth, and also assessed p21 WAF1 mRNA, transcriptional activation, and protein levels. BMP2 increased nuclear phospho-SMAD1 2-fold, which increased another 2-3 fold when RAS/ERK was inhibited. BMP2 increased BMP-specific SMAD transcriptional activity 2-fold over control and decreased cell growth, but inhibition of RAS/ERK further enhanced BMP-specific transcriptional activity by an additional 1.5-2 fold and enhanced growth suppression by 20%. BMP-induced growth suppression is mediated in part by p21 WAF1 , not by transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS/ERK. In colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21 WAF1 but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway.

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Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers

Cited by 123 publications

References 13 publications

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

Activin Type 2 Receptor Restoration in MSI-H Colon Cancer Suppresses Growth and Enhances Migration With Activin

Unregulated smooth-muscle myosin in human intestinal neoplasia

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

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