Identification of a Putative Tumor Suppressor Gene <i>Rap1GAP</i> in Pancreatic Cancer

Zhang, Lizhi; Li, Chenwei; Mahmood, Redah; Golen, Kenneth van; Greenson, Joel; Li, Gangyong; D’Silva, Nisha J.; Li, Xiangquan; Burant, Charles F.; Logsdon, Craig D.; Simeone, Diane M.

doi:10.1158/0008-5472.can-05-3025

Cited by 80 publications

(122 citation statements)

References 34 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…As previously reported (37,47,53), stromal cells did not stain for Rap1GAP. Rap1GAP staining was decreased in the majority (12/15) of the tumors analyzed (Fig.…”

supporting

confidence: 83%

“…Overexpression of Rap1GAP in oropharyngeal squamous cell (54) and pancreatic (53) carcinoma lines impaired tumor formation in mouse xenograft models. In vitro, overexpression of Rap1GAP impaired tumor cell proliferation (34,47,53,54,56) and enhanced apoptosis (34,53,56). In some instances, overexpression of Rap1GAP inhibited tumor cell migration and invasion (3,47,53,56), while in others, it enhanced invasion (34).…”

mentioning

confidence: 99%

“…Rap1GAP protein levels are decreased in pancreatic adenocarcinomas (53), papillary thyroid carcinomas (37,47,57), and melanomas (56). Rap1GAP downregulation has been shown to arise as a consequence of proteasomal degradation (46), loss of heterozygosity (37,53), and promoter methylation (56,57).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Downregulation of Rap1GAP in Human Tumor Cells Alters Cell/Matrix and Cell/Cell Adhesion

Tsygankova

Tang

et al. 2010

Molecular and Cellular Biology

View full text Add to dashboard Cite

Rap1GAP expression is decreased in human tumors. The significance of its downregulation is unknown. We show that Rap1GAP expression is decreased in primary colorectal carcinomas. To elucidate the advantages conferred on tumor cells by loss of Rap1GAP, Rap1GAP expression was silenced in human colon carcinoma cells. Suppressing Rap1GAP induced profound alterations in cell adhesion. Rap1GAP-depleted cells exhibited defects in cell/cell adhesion that included an aberrant distribution of adherens junction proteins. Depletion of Rap1GAP enhanced adhesion and spreading on collagen. Silencing of Rap expression normalized spreading and restored E-cadherin, ␤-catenin, and p120-catenin to cell/cell contacts, indicating that unrestrained Rap activity underlies the alterations in cell adhesion. The defects in adherens junction protein distribution required integrin signaling as E-cadherin and p120-catenin were restored at cell/cell contacts when cells were plated on poly-L-lysine. Unexpectedly, Src activity was increased in Rap1GAP-depleted cells. Inhibition of Src impaired spreading and restored E-cadherin at cell/cell contacts. These findings provide the first evidence that Rap1GAP contributes to cell/cell adhesion and highlight a role for Rap1GAP in regulating cell/matrix and cell/cell adhesion. The frequent downregulation of Rap1GAP in epithelial tumors where alterations in cell/cell and cell/matrix adhesion are early steps in tumor dissemination supports a role for Rap1GAP depletion in tumor progression.Mammalian Rap proteins Rap1a/b and Rap2a/b/c are members of the Ras superfamily of small GTPases. Rap proteins are active when bound to GTP and inactive when bound to GDP. Cellular Rap activity is regulated by the concerted action of guanine nucleotide exchange factors that activate Rap (RapGEFs) and Rap-specific GTPaseactivating proteins (RapGAPs) that inactivate Rap (reviewed in reference 10). The Rap1GAP family is composed of several members, including Rap1GAP, Rap1GAPII, Spa-1/SIPA1, and E6TP1/SIPA1L1. Several lines of evidence suggest that RapGAPs function as tumor and/or invasion suppressors. Downregulation of E6TP1 by human papillomavirus protein E6 contributes to cervical cancer (20, 21), and Spa-1 deficiency in mice induces a spectrum of myelodysplastic disorders similar to chronic myelogenous leukemia (26). The SPA1 gene was identified as a candidate for the metastasis efficiency modifier locus in mice (38). Although the relevance of this observation to humans is not yet clear, single-nucleotide polymorphisms in the SPA1 gene in human breast tumors have been associated with lymph node involvement and poor survival (15). Intriguingly, Spa-1 interacts with Brd4 (18) and Rrp-1b (13), the protein products of genes associated with patterns of extracellular matrix protein gene expression characteristic of metastatic tumors (14).The RAP1GAP gene maps to 1p35-36, a chromosomal region subject to copy number alterations in human tumors (36, 49). Rap1GAP protein levels are decreased in pancreatic adenocarcinomas (53), pap...

show abstract

“…As previously reported (37,47,53), stromal cells did not stain for Rap1GAP. Rap1GAP staining was decreased in the majority (12/15) of the tumors analyzed (Fig.…”

supporting

confidence: 83%

mentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of Rap1GAP in Human Tumor Cells Alters Cell/Matrix and Cell/Cell Adhesion

Tsygankova

Tang

et al. 2010

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…7A) and previous studies suggest Rap1GAP and its family members Rap1GAPII, Spa1/SIPA1, and E6TP1 possess tumor metastasis suppressor activities. Rap1GAP protein levels are decreased in several types of cancer, including pancreatic adenocarcinoma (55), papillary thyroid carcinoma (56,57), colorectal carcinoma (58), and melanoma (59). The implication of Rap1GAP as a tumor suppressor was largely deduced based upon experimental results using forced overexpression of full-length Rap1GAP (60,61).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Regulates Renal Cell Carcinoma Invasion through the EP4 Receptor-Rap GTPase Signal Transduction Pathway

Zhang

Frilot

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prognosis for patients with early stage kidney cancer has improved, but the treatment options for patients with locally advanced disease and metastasis remain few. Understanding the molecular mechanisms that regulate invasion and metastasis is critical for developing successful therapies to treat these patients. Proinflammatory prostaglandin E 2 plays an important role in cancer initiation and progression via activation of cognate EP receptors that belong to the superfamily of G proteincoupled receptors. Here we report that prostaglandin E 2 promotes renal cancer cell invasion through a signal transduction pathway that encompasses EP4 and small GTPase Rap. Inactivation of Rap signaling with Rap1GAP, like inhibition of EP4 signaling with ligand antagonist or knockdown with shRNA, reduces the kidney cancer cell invasion. Human kidney cells evidence increased EP4 and decreased Rap1GAP expression levels in the malignant compared with benign samples. These results support the idea that targeted inhibition of EP4 signaling and restoration of Rap1GAP expression constitute a new strategy to control kidney cancer progression.

show abstract

“…Increased Rap activation is associated with enhanced invasiveness in several types of tumors. 45,46 If this were true for B-cell lymphomas, then Rap-GTP levels could be a useful prognostic marker for aggressive lymphomas, in addition to being a potential therapeutic target. lymphomas to form solid tumors at secondary sites in vivo.…”

mentioning

confidence: 99%