RRIG1 mediates effects of retinoic acid receptor beta2 on tumor cell growth and gene expression through binding to and inhibition of RhoA.
The expression of retinoic acid receptor beta2 (RAR-beta2) is frequently lost in various cancers and their premalignant lesions. However, the restoration of RAR-beta2 expression inhibits tumor cell growth and suppresses cancer development. To understand the molecular mechanisms responsible for this RAR-beta2-mediated antitumor activity, we did restriction fragment differential display-PCR and cloned a novel retinoid receptor-induced gene 1 (RRIG1), which is differentially expressed in RAR-beta2-positive and RAR-beta2-negative tumor cells. RRIG1 cDNA contains 2,851 bp and encodes a protein with 276 amino acids; the gene is localized at chromosome 9q34. Expressed in a broad range of normal tissues, RRIG1 is also lost in various cancer specimens. RRIG1 mediates the effect of RAR-beta2 on cell growth and gene expression (e.g., extracellular signal-regulated kinase 1/2 and cyclooxygenase-2). The RRIG1 protein is expressed in the cell membrane and binds to and inhibits the activity of a small GTPase RhoA. Whereas induction of RRIG1 expression inhibits RhoA activation and f-actin formation and consequently reduces colony formation, invasion, and proliferation of esophageal cancer cells, antisense RRIG1 increases RhoA activity and f-actin formation and thus induces the colony formation, invasion, and proliferation of these cells. Our findings therefore show a novel molecular pathway involving RAR-beta2 regulation of RRIG1 expression and RRIG1-RhoA interaction. An understanding of this pathway may translate into better control of human cancer.
Liang
Zheng D
ZD
Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lippman
Scott M
SM
Wu
Tsung-Teh
TT
Lotan
Reuben
R
Xu
Xiao-Chun
XC
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018076:DNA, Complementary; D008565:Membrane Proteins; D012333:RNA, Messenger; C513407:RRIG1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein