Retinoid-responsive transcriptional changes in epidermal keratinocytes.
Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48, and 72 h, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis.
Lee
Ding-Dar
DD
New York University School of Medicine, Departments of Dermatology, Biochemistry and The Cancer Institute, New York, New York 10016.|Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Dermatology, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Stojadinovic
Olivera
O
Department of Dermatology & Cutaneous Surgery, Wound Healing and Regenerative Medicine Program, University of Miami Miller School of Medicine, Miami, Florida.|Hospital for Special Surgery at Weill Medical College of Cornell University, Tissue Repair Lab, Tissue Engineering, Regeneration and Repair Program, New York, New York 10021.
Krzyzanowska
Agata
A
Hospital for Special Surgery at Weill Medical College of Cornell University, Tissue Repair Lab, Tissue Engineering, Regeneration and Repair Program, New York, New York 10021.
Vouthounis
Constantinos
C
Hospital for Special Surgery at Weill Medical College of Cornell University, Tissue Repair Lab, Tissue Engineering, Regeneration and Repair Program, New York, New York 10021.
Blumenberg
Miroslav
M
New York University School of Medicine, Departments of Dermatology, Biochemistry and The Cancer Institute, New York, New York 10016.
Tomic-Canic
Marjana
M
Department of Dermatology & Cutaneous Surgery, Wound Healing and Regenerative Medicine Program, University of Miami Miller School of Medicine, Miami, Florida.|Hospital for Special Surgery at Weill Medical College of Cornell University, Tissue Repair Lab, Tissue Engineering, Regeneration and Repair Program, New York, New York 10021.|Department of Dermatology, Weill Medical College of the Cornell University, New York, New York 10021.
D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D000078404:Epidermal Cells; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007633:Keratins / Q000235:genetics; D007641:Keratolytic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011565:Psoriasis / Q000235:genetics / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
D007641:Keratolytic Agents; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D007633:Keratins