Retinoids suppress proliferation, induce cell spreading, and up-regulate connexin43 expression only in postconfluent 10T1/2 cells: implications for the role of gap junctional communication.
The antiproliferative actions of retinoids in the C3H/10T1/2 cell system are exhibited as a decrease in proliferation rate and a decreased cell saturation density at confluence. These actions correlate with up-regulated gap junctional communication (GJC) driven by the retinoid-induced increased expression of the gap junctional protein connexin43 (Cx43). Here we examine which actions of retinoids occur only in cells making extensive intercellular contacts, and thus may be mediated through GJC, and which are exhibited in the absence of extensive intercellular contacts and thus may be independent of GJC. In confluent cultures, the synthetic retinoid tetrahydrotetramethylnapthalenyl-propenylbenzoic acid (TTNPB) increased GJC, reduced the already low [3H]thymidine-labeling index of G1 growth-arrested confluent cells from 4.2 to < 0.1%, and increased the area occupied by each cell by 42%. In contrast, none of these parameters was altered in logarithmic growth phase cells with very limited intercellular contacts. In order to separate cell-cell contact from cell cycle-related phenomena, non-contacting cells were arrested in early G1 by lovastatin. In this situation, Cx43 expression was low and inducible by retinoids, as in G1/G0 growth-arrested confluent cells; however, no cell spreading was induced by TTNPB. In contrast, in non-contacting cycling cells or in cells arrested by aphidicolin, Cx43 expression was higher than in confluent cells. In this situation, TTNPB did not induce Cx43 and did not induce spreading. These data demonstrate the cell cycle phase dependence of connexin43 expression and of retinoid action.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular Oncology Program, Cancer Research Center of Hawaii, Honolulu 96813.
M Z
MZ
Hossain
J S
JS
Bertram
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D018031:Connexin 43 / Q000032:analysis / Q000096:biosynthesis*; D003593:Cytoplasm / Q000737:chemistry; D015536:Down-Regulation; D017629:Gap Junctions / Q000187:drug effects*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D018031:Connexin 43; D012333:RNA, Messenger; D012176:Retinoids; D016590:Aphidicolin; D008148:Lovastatin