Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors.
Transcriptional activation of the nuclear receptor RAR by retinoic acid (RA) often leads to inhibition of cell growth. However, in some tissues, RA promotes cell survival and hyperplasia, activities that are unlikely to be mediated by RAR. Here, we show that, in addition to functioning through RAR, RA activates the "orphan" nuclear receptor PPARbeta/delta, which, in turn, induces the expression of prosurvival genes. Partitioning of RA between the two receptors is regulated by the intracellular lipid binding proteins CRABP-II and FABP5. These proteins specifically deliver RA from the cytosol to nuclear RAR and PPARbeta/delta, respectively, thereby selectively enhancing the transcriptional activity of their cognate receptors. Consequently, RA functions through RAR and is a proapoptotic agent in cells with high CRABP-II/FABP5 ratio, but it signals through PPARbeta/delta and promotes survival in cells that highly express FABP5. Opposing effects of RA on cell growth thus emanate from alternate activation of two different nuclear receptors.
Schug
Thaddeus T
TT
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA.
Berry
Daniel C
DC
Shaw
Natacha S
NS
Travis
Skylar N
SN
Noy
Noa
N
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D015603:Keratinocytes; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D048068:PPAR-beta / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*
C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins; D048068:PPAR-beta; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin