A Functional Polymorphism in <b>
                     <i>RGS6</i>
                  </b> Modulates the Risk of Bladder Cancer

Berman, David M.; Wang, Yunfei; Liu, Zhengyu; Dong, Qiong; Burke, Laura; Liotta, Lance A.; Fisher, Rory A.; Wu, Xifeng

doi:10.1158/0008-5472.can-04-1916

Cited by 56 publications

(48 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…RGS20 belongs to a family of proteins with conserved GTPase-activating domain of approximately 120 amino acid residues. Previously, polymorphisms of RGS2 and RGS6 genes were described in bladder and lung cancers (53,54). RGS20 itself was reported in stabilizing the microtubule filaments (55).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

View full text Add to dashboard Cite

Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastaticassociated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.

show abstract

Section: Discussionmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…The possibility that RGS6 might possess antiproliferative actions was first suggested by the finding that a SNP in RGS6 that increased its translation ϳ3-fold was associated with significant reduction in the risk of bladder cancer in humans (18). This observation provided the first link between RGS proteins and cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Although the precise physiological role of RGS6 is unknown, RGS6 has been linked to cellular stress responses and can derepress transcriptional inhibition by DMAP1 (DNA methyltransferase 1-associated protein) (16,17). A link between RGS6 and cancer was suggested by the finding that a SNP in the human RGS6 gene, which increases translational efficiency ϳ3-fold, is associated with an overall reduction in the risk of bladder tumor formation (18). Based upon the known role of RGS6 as a G protein GAP, the link between G proteins and cancer, and the reduction of cancer risk with increased expression of RGS6, we hypothesized that RGS6 might function to inhibit growth of cancer cells.…”

mentioning

confidence: 99%

Regulator of G Protein Signaling 6 (RGS6) Induces Apoptosis via a Mitochondrial-dependent Pathway Not Involving Its GTPase-activating Protein Activity

Maity¹,

Yang²,

Huang³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Regulator of G protein signaling 6 (RGS6) is a member of a family of proteins called RGS proteins, which function as GTPase-activating proteins (GAPs) for G␣ subunits. Given the role of RGS6 as a G protein GAP, the link between G protein activation and cancer, and a reduction of cancer risk in humans expressing a RGS6 SNP leading to its increased translation, we hypothesized that RGS6 might function to inhibit growth of cancer cells. Here, we show a marked down-regulation of RGS6 in human mammary ductal epithelial cells that correlates with the progression of their transformation. RGS6 exhibited impressive antiproliferative actions in breast cancer cells, including inhibition of cell growth and colony formation and induction of cell cycle arrest and apoptosis by mechanisms independent of p53. RGS6 activated the intrinsic pathway of apoptosis involving regulation of Bax/Bcl-2, mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, activation of caspases-3 and -9, and poly(ADP-ribose) polymerase cleavage. RGS6 promoted loss of mitochondrial membrane potential (⌬⌿ m ) and increases in reactive oxygen species (ROS). RGS6-induced caspase activation and loss of ⌬⌿ m was mediated by ROS, suggesting an amplification loop in which ROS provided a feed forward signal to induce MOMP, caspase activation, and cell death. Loss of RGS6 in mouse embryonic fibroblasts dramatically impaired doxorubicin-induced growth suppression and apoptosis. Surprisingly, RGS6-induced apoptosis in both breast cancer cells and mouse embryonic fibroblasts does not require its GAP activity toward G proteins. This work demonstrates a novel signaling action of RGS6 in cell death pathways and identifies it as a possible therapeutic target for treatment of breast cancer. Regulator of G protein signaling (RGS)2 proteins comprise a family of proteins, defined by the presence of a semiconserved region called the RGS domain, which negatively regulate heterotrimeric G protein signaling (1-3). These proteins were discovered as essential negative regulators of heterotrimeric G protein signaling by genetic studies in yeast followed by similar studies in Caenorhabditis elegans (4 -6). RGS proteins function as GTPase-activating proteins (GAPs) for heterotrimeric G protein subunits (7,8), an activity bestowed by their RGS domain (9) thereby enhancing the shut-off mechanism for G protein signaling. Thirty mammalian genes encode proteins with the hallmark RGS domain or less closely related versions of this domain, and RGS proteins have been classified into subfamilies based upon sequence similarities within the RGS domain that extend to sequences outside of this domain (2, 8). RGS6 is a member of the R7 subfamily of proteins that possess, in addition to their RGS domain, a GGL (G ␥ subunit-like) domain that allows for association with G␤ 5 and stabilization of RGS6 and a Drosophila/EGL10/Pleckstrin homology/DEP helical extension (DEP/DHEX) domain that allows for association with one of two additional proteins, R7BP or R9AP, and is thought to pr...

show abstract

“…Previous studies have had inconsistent results for an association of the CCND1 A870G polymorphism with bladder cancer (Cortessis et al, 2003;Wang et al, 2003b;Berman et al, 2004;Ito et al, 2004), endometrial cancer (Kang et al, 2005), breast cancer (Grieu et al, 2003;Krippl et al, 2003;Shu et al, 2005), head and neck cancer (Zheng et al, 2001), gastric and oesophageal cancer (Wang et al, 2003c;Zhang et al, 2003a), hepatocellular carcinoma (Zhang et al, 2003b), lung cancer (Qiuling et al, 2003), and prostate cancer (Koike et al, 2003;Wang et al, 2003a). The strongest evidence, to date, has linked the CCND1 A870G polymorphism with an increased risk of colorectal cancer and adenoma in many (Kong et al, 2000(Kong et al, , 2001Bala and Peltomaki, 2001;Porter et al, 2002) though not all studies (McKay et al, 2000).…”

mentioning

confidence: 99%

Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

et al. 2006

View full text Add to dashboard Cite

Cyclin D1 (CCND1) plays a key role in cell cycle control, particularly in the transition from G 1 to S phase, which is regulated by cyclindependent kinases. A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies. Among subjects with hereditary nonpolyposis colorectal cancer, the A870G polymorphism has also been associated with a younger age of onset of colorectal cancer. We analysed 181 colorectal cancer cases and 475 matched controls and 524 adenoma cases and 517 matched controls within women in the Nurses' Health Study (NHS) cohort, 171 colorectal cancer cases and 347 matched controls and 372 adenoma cases and 712 matched controls nested within men in the Health Professionals' Follow-Up Study (HPFS) cohort, and 258 colorectal cancer cases and 415 matched controls within men in the Physicians' Health Study (PHS) cohort to assess the risk associated with the CCND1 A870G genotype. Moreover, we assessed whether CCND1 genotype modified the effect of a sporadic (nonsyndromic) family history of colorectal cancer as well as the effect of other dietary and lifestyle risk factors for colorectal cancer and adenoma. In all cohorts combined, the CCND1 polymorphism did not show statistically significant associations to risk of colorectal cancer (odds ratio (OR) for A allele carriers, 1.04; 95% confidence interval (95% CI), 0.82 -1.32) or adenoma (OR, 0.96; 95% CI, 0.79 -1.18). The CCND1 A870G genotype was associated with a modest, although nonsignificantly elevated risk of colorectal cancer (OR, 1.59; 95% CI, 0.98 -2.57) in women. In contrast, the polymorphism was not associated with increased risk of adenoma in either men or women. Among participants with the A870G genotype, a family history of colorectal cancer conferred a substantially greater risk of colorectal cancer in the women (P for interaction ¼ 0.06) and adenoma in the men (P for interaction ¼ 0.02). Current postmenopausal hormone (PMH) use was associated with a significant reduction in the risk of colorectal cancer and adenoma among women with the A870G genotype, whereas there was no effect of PMH use among those with the GG genotype. The CCND1 polymorphism appeared to confer a modest elevation in the risk of colorectal cancer among women. Moreover, the A870G genotype may enhance the protective effect of postmenopausal oestrogen use on the development of colorectal neoplasia.

show abstract

A Functional Polymorphism in RGS6 Modulates the Risk of Bladder Cancer

Cited by 56 publications

References 44 publications

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Regulator of G Protein Signaling 6 (RGS6) Induces Apoptosis via a Mitochondrial-dependent Pathway Not Involving Its GTPase-activating Protein Activity

Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

Contact Info

Product

Resources

About