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SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers. Cell Cycle 2014;13(6):941-52

Date

02/21/2014

Pubmed ID

24552806

Pubmed Central ID

PMC3984317

DOI

10.4161/cc.27804

Scopus ID

2-s2.0-84897979722 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Schuld NJ, Hauser AD, Gastonguay AJ, Wilson JM, Lorimer EL, Williams CL

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Carcinoma, Non-Small-Cell Lung
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cyclin D1
Female
Guanine Nucleotide Exchange Factors
Heterografts
Humans
Lung Neoplasms
Mice
Mice, SCID
Pancreatic Neoplasms
Proliferating Cell Nuclear Antigen
Protein Isoforms
rho GTP-Binding Proteins