Direct Interaction of Tumor Suppressor CEACAM1 with Beta Catenin: Identification of Key Residues in the Long Cytoplasmic Domain

Liu, Jin; Li, Yun; Chen, Charng-Jui; Sherman, Mark A.; Le, Keith; Shively, John E.

doi:10.3181/0712-rm-352

Cited by 32 publications

(57 citation statements)

References 62 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…How MiniSOX9, devoid of transactivation domain, can activate Wnt? It might be a consequence of SOX9 inhibition, because SOX9 upregulates ICAT (inhibitor of b-catenin and T-cell factor (TCF))/TCF interaction (Tago et al, 2000) and the Groucho-related corepressors TLE2-4 (Cavallo et al, 1998;Roose et al, 1998) in HT29Cl.16E cells (Bastide et al, 2007), as well as CEACAM1 , which binds to the armadillo repeats of b-catenin, thereby inducing its redistribution from the cytosol to the plasma membrane (Jin et al, 2008;Leung et al, 2008). Moreover, MiniSOX9 is able to activate the Wnt pathway on its own, through its capacity to bind to b-catenin and inducing b-catenin accumulation in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

MiniSOX9, a dominant-negative variant in colon cancer cells

et al. 2011

View full text Add to dashboard Cite

Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by realtime reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Ca promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

MiniSOX9, a dominant-negative variant in colon cancer cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Jin et al (2008) have recently shown that CEACAM1-L directly associates with the b-catenin armadillo repeats. We have confirmed this finding and shown that CEACAM1-L binds to and colocalizes with b-catenin in colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…We thus examined expression and activity levels of key intestinal proteins in the Wnt signaling pathway as it usually sustains major alterations in intestinal cancer. In fact, Jin et al (2008) have recently shown by coimmunoprecipitation, glutathione-S-transferase (GST) pulldowns, mutational analyses, BiACore analyses and colocalization in breast cancer cells and human T lymphocytes that residues within the long cytoplasmic domain of human CEACAM1-L bind directly to the armadillo repeats of b-catenin. To verify expression or activity of key signaling proteins, cytosolic and nuclear fractions of total intestines were prepared ( Figure 3) and purity of these fractions was monitored by immunoblotting all intestinal samples with antibodies to HSP90 for cytosolic or laminB1 for nuclear fractions.…”

Section: Extra-intestinal Lesions Are Increased Inmentioning

confidence: 99%

Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

et al. 2008

View full text Add to dashboard Cite

The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is downregulated in colonic and intestinal hyperplastic lesions as well as in other cancers, where it functions as a tumor suppressor. To investigate the functions of CEACAM1 in the normal intestine and in intestinal tumors, we generated a compound knockout mouse model and examined both Ceacam1 À/À and Apc 1638N/ þ :Ceacam1 À/À mice. Ceacam1 À/À intestinal cells exhibited a significant decrease in apoptosis, with no change in proliferation or migration, however. Compound Apc 1638N/ þ :Ceacam1 À/À mice demonstrated an increase in intestinal tumor multiplicity and tumor progression. Increases in intussusceptions and desmoid lesions were also observed. We have shown that CEACAM1-L associates with b-catenin by co-immunoprecipitation and colocalization in CEACAM1-L-transfected CT26 and CT51 mouse colon carcinoma cells. Ceacam1 À/À enterocytes displayed decreased glycogen synthase kinase 3-b activity with corresponding nuclear localization of b-catenin. Increased T-cell factor/Lef transcriptional activity was observed in CEACAM1-null CT51 colonic cells and in Caco2 colon cancer cells in which CEACAM1 was downregulated. A significant increased expression in c-Myc and cyclin D1 targets of the Wnt signaling pathway was also revealed in the Ceacam1 À/À intestine. CEACAM1 therefore actively participates in Wnt signaling in intestinal cells and its downregulation in intestinal tissue contributes to malignancy by augmenting tumor multiplicity and progression.

show abstract

“…the binding of SOX9 to DNA (Bastide et al, 2007). This inhibition might result from an upregulation of groucho-related inhibitors of the β-catenin-Tcf complex (Bastide et al, 2007) and of CEACAM1, a direct SOX9 target (Jin et al, 2008;Leung et al, 2008;Zalzali et al, 2008). Indeed, the W143R SOX9 mutant, which is unable to bind DNA, is unable to inhibit the Wnt-APC pathway, although it is able to repress PKCα expression, as shown in the present study.…”

Section: Sox9-dependent Pkcα Repression Involves Sp1mentioning

confidence: 54%

A new mechanism of SOX9 action to regulate PKCα expression in the intestine epithelium

Dupasquier

Abdel-Samad

Glazer

et al. 2009

Journal of Cell Science

View full text Add to dashboard Cite

Variations of protein kinase C (PKC) expression greatly influence the proliferation-to-differentiation transition (PDT) of intestinal epithelial cells and might have an important impact on intestinal tumorigenesis. We demonstrate here that the expression of PKCα in proliferating intestinal epithelial cells is repressed both in vitro and in vivo by the SOX9 transcription factor. This repression does not require DNA binding of the SOX9 high-mobility group (HMG) domain but is mediated through a new mechanism of SOX9 action requiring the central and highly conserved region of SOXE members. Because SOX9 expression is itself upregulated by Wnt-APC signaling in intestinal epithelial cells, the present study points out this transcription factor as a molecular link between the Wnt-APC pathway and PKCα. These results provide a potential explanation for the decrease of PKCα expression in colorectal cancers with constitutive activation of the Wnt-APC pathway.

show abstract

Direct Interaction of Tumor Suppressor CEACAM1 with Beta Catenin: Identification of Key Residues in the Long Cytoplasmic Domain

Cited by 32 publications

References 62 publications

MiniSOX9, a dominant-negative variant in colon cancer cells

MiniSOX9, a dominant-negative variant in colon cancer cells

Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

A new mechanism of SOX9 action to regulate PKCα expression in the intestine epithelium

Contact Info

Product

Resources

About