Suprabasal expression of a dominant-negative RXR alpha mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids

被引:57
作者
Feng, X
Peng, ZH
Di, W
Li, XY
RochetteEgly, C
Chambon, P
Voorhees, JJ
Xiao, JH
机构
[1] UNIV MICHIGAN, DEPT DERMATOL, ANN ARBOR, MI 48109 USA
[2] INST GENET & BIOL MOL & CELLULAIRE, INSERM, CNRS, U184, LGME, F-67404 ILLKIRCH GRAFFENSTADEN, FRANCE
关键词
retinoids; 9-cis retinoic acid receptor; transgenic mouse; epidermal keratinocytes; gene transcription; cell proliferation;
D O I
10.1101/gad.11.1.59
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
To determine whether 9-cis retinoic acid receptors (RXRs) regulate the biological activity of all-trans retinoic acid (tRA) and its receptors (RARs) in skin, we have targeted a dominant-negative RXR alpha (dnRXR alpha) lacking transactivation function AF-2 to differentiated suprabasal keratinocytes in the epidermis of transgenic mice. Driven by the suprabasal-specific keratin-10 gene promoter, expression of dnRXR alpha severely reduced the ability of RAR-selective ligands tRA and CD367 to induce epidermal mRNA levels of the CRABPII, CRBPI, and CRBPII genes, which contain RA-responsive elements (RAREs) DR1 and/or DR2. It also reduced gene-specific, synergistic induction of CRBPI mRNA by a combination of CD367 and RXR-selective SR11237. Like endogenous RXR alpha, dnRXRa in epidermal nuclear extracts from the transgenic mice competitively formed heterodimers with endogenous RAR gamma on RAREs, suggesting that dnRXR alpha impairs retinoid signaling by competing with endogenous RAR gamma-RXR alpha heterodimers. Histologically, the epidermis of dnRXR alpha. mice showed no detectable developmental abnormalities. Surprisingly, in adult animals, the suprabasal expression of dnRXR alpha significantly reduced the ability of topically applied tRA to stimulate proliferation of undifferentiated keratinocytes in the basal layer of epidermis. RXR-selective ligands alone had no detectable effects on both normal and transgenic mouse epidermis. Accordingly, we suggest that in vivo: (1) in suprabasal keratinocytes, retinoids regulate gene transcription via RAR-RXR heterodimers in which RAR confers a predominant ligand response, whereas RXR AF-2 is required for liganded RAR AE-2 to efficiently trans-activate target genes, and (2) this suprabasal RXR-assisted mechanism indirectly regulates proliferation of basal keratinocytes likely via intercellular signaling.
引用
收藏
页码:59 / 71
页数:13
相关论文
共 38 条
  • [21] THE RXR HETERODIMERS AND ORPHAN RECEPTORS
    MANGELSDORF, DJ
    EVANS, RM
    [J]. CELL, 1995, 83 (06) : 841 - 850
  • [22] PROLIFERATIVE RESPONSES OF THE SKIN TO EXTERNAL STIMULI
    MARKS, F
    FURSTENBERGER, G
    [J]. ENVIRONMENTAL HEALTH PERSPECTIVES, 1993, 101 : 95 - 101
  • [23] RARS AND RXRS - EVIDENCE FOR 2 AUTONOMOUS TRANSACTIVATION FUNCTIONS (AF-1 AND AF-2) AND HETERODIMERIZATION INVIVO
    NAGPAL, S
    FRIANT, S
    NAKSHATRI, H
    CHAMBON, P
    [J]. EMBO JOURNAL, 1993, 12 (06) : 2349 - 2360
  • [24] NAKSHATRI H, 1994, J BIOL CHEM, V269, P890
  • [25] PECK GL, 1994, RETINOIDS BIOL CHEM, P209
  • [26] Regulation of metabolism by retinoic acid and its nuclear receptors
    Pfahl, M
    Chytil, F
    [J]. ANNUAL REVIEW OF NUTRITION, 1996, 16 : 257 - 283
  • [27] RETINOIC ACID RECEPTOR-GAMMA - SPECIFIC IMMUNODETECTION AND PHOSPHORYLATION
    ROCHETTEEGLY, C
    LUTZ, Y
    SAUNDERS, M
    SCHEUER, I
    GAUB, MP
    CHAMBON, P
    [J]. JOURNAL OF CELL BIOLOGY, 1991, 115 (02) : 535 - 545
  • [28] DETECTION OF RETINOID-X RECEPTORS USING SPECIFIC MONOCLONAL AND POLYCLONAL ANTIBODIES
    ROCHETTEEGLY, C
    LUTZ, Y
    PFISTER, V
    HEYBERGER, S
    SCHEUER, I
    CHAMBON, P
    GAUB, MP
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 204 (02) : 525 - 536
  • [29] ROY DY, 1995, MOL CELL BIOL, V15, P6481
  • [30] INHIBITION OF SKIN DEVELOPMENT BY TARGETED EXPRESSION OF A DOMINANT-NEGATIVE RETINOLE ACID RECEPTOR
    SAITOU, M
    SUGAI, S
    TANAKA, T
    SHIMOUCHI, K
    FUCHS, E
    NARUMIYA, S
    KAKIZUKA, A
    [J]. NATURE, 1995, 374 (6518) : 159 - 162