title: SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers.
abstract: Oncogenic mutation or misregulation of small GTPases in the Ras and Rho families can promote unregulated cell cycle progression in cancer. Post-translational modification by prenylation of these GTPases allows them to signal at the cell membrane. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, promote the prenylation and membrane trafficking of multiple Ras and Rho family members, which makes SmgGDS a potentially important regulator of the cell cycle. Surprisingly little is known about how SmgGDS-607 and SmgGDS-558 affect cell cycle-regulatory proteins in cancer, even though SmgGDS is overexpressed in multiple types of cancer. To examine the roles of SmgGDS splice variants in the cell cycle, we compared the effects of the RNAi-mediated depletion of SmgGDS-558 vs. SmgGDS-607 on cell cycle progression and the expression of cyclin D1, p27, and p21 in pancreatic, lung, and breast cancer cell lines. We show for the first time that SmgGDS promotes proliferation of pancreatic cancer cells, and we demonstrate that SmgGDS-558 plays a greater role than SmgGDS-607 in cell cycle progression as well as promoting cyclin D1 and suppressing p27 expression in multiple types of cancer. Silencing both splice variants of SmgGDS in the cancer cell lines produces an alternative signaling profile compared with silencing SmgGDS-558 alone. We also show that loss of both SmgGDS-607 and SmgGDS-558 simultaneously decreases tumorigenesis of NCI-H1703 non-small cell lung carcinoma (NSCLC) xenografts in mice. These findings indicate that SmgGDS promotes cell cycle progression in multiple types of cancer, making SmgGDS a valuable target for cancer therapeutics.
authors.affiliation: Department of Pharmacology and Toxicology; Medical College of Wisconsin; Milwaukee, WI USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Schuld
authors.affiliation: Department of Pharmacology and Toxicology; Medical College of Wisconsin; Milwaukee, WI USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.affiliation: Department of Pediatrics; Medical College of Wisconsin; Milwaukee, WI USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Gastonguay
authors.affiliation: Department of Pharmacology and Toxicology; Medical College of Wisconsin; Milwaukee, WI USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Department of Pharmacology and Toxicology; Medical College of Wisconsin; Milwaukee, WI USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Lorimer
authors.affiliation: Department of Pharmacology and Toxicology; Medical College of Wisconsin; Milwaukee, WI USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D018809:Proliferating Cell Nuclear Antigen; D020033:Protein Isoforms; C115955:RAP1GDS1 protein, human; C413374:p27 antigen; D019938:Cyclin D1; D020741:rho GTP-Binding Proteins
keywords: GTPase; RNAi; Rap1GDS1; SmgGDS; breast cancer; cell cycle; lung cancer; mouse tumorigenesis; pancreatic cancer; proliferation