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DAX1, an unusual member of the nuclear receptor superfamily with diverse functions

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Abstract

Nuclear receptors (NRs) act as ligand-activated transcription factors and play an important role in regulating metabolism, homeostasis, differentiation, development, and pathogenesis of various diseases. Once activated by a ligand, a NR binds to a specific nucleotide sequence in a target gene to activate its expression. Natural ligands are known for the majority of NRs. DAX1 is an unusual member of the NR superfamily, lacking a ligand and a typical DNA-binding domain. DAX1 was found to play an important role in regulating the development of the adrenals and gonads as early as 20 years ago, but the molecular mechanisms of its effect were unclear. DAX1 is capable of interacting with many members of the NR superfamily and with various transcriptional corepressors and coactivators, and its functions are not restricted to regulating the adrenal and gonadal development and contributing to steroidogenesis. Recent studies elucidated the role DAX1 plays in the pathogenesis of X-linked adrenal hypoplasia and dosage-sensitive sex reversal. DAX1 is an important component of the transcription factor network that maintains the pluripotent state of mouse embryonic stem cells. Modern data on the properties, functions, and mechanisms of action of DAX1 are considered in the review. Specifics of the DAX1 interactions with various protein partners are characterized. Examples are provided to illustrate the corepressor and coactivator effects of DAX1 on target gene transcription. In addition, the review discusses the role DAX1 plays in the pathogenesis of hereditary disorders, a possible association of DAX1 with endocrine oncology diseases, and the contribution of DAX1 to self-renewal of mouse embryonic stem cells.

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Abbreviations

AR:

androgen receptor

DBD:

DNA-binding domain

EGF:

epidermal growth factor

ER:

estrogen receptor

ERRγ:

estrogen-related receptor γ

EWS:

Ewing sarcoma gene

FXR:

farnesoid X receptor

GR:

glucocorticoid receptor

GRIP1:

glucocorticoid receptor-interacting protein 1

HNF4α:

hepatocyte nuclear factor 4α

LBD:

ligand-binding domain

LEF:

lymphoid enhancer-binding factor

LRH1:

liver receptor homolog 1

LXRα:

liver X receptor α

MC2R:

melanocortin receptor 2

MAPK:

mitogen-activated protein kinase

NF-κB:

nuclear factor κB

NR:

nuclear receptor

Nur77 (NR4A2):

nerve growth factor IB receptor

N-CoR:

nuclear receptor corepressor 1

PPARγ:

peroxisome proliferator-activated receptor γ

PGC-1:

PPAR coactivator 1

PR:

progesterone receptor

RAC-3:

ras-related C3 botulinum toxin substrate 3

RNF31:

ring finger protein 31

SF1:

steroidogenic factor 1

SMRT:

silencing mediator of retinoic acid and thyroid hormone receptor

SOX9:

SRY-related HMG-box protein 9

SRA:

steroid receptor RNA activator

SRC-1:

steroid receptor coactivator 1

SREBP1c:

sterol regulatory element-binding protein 1

SRY:

sex-determining region Y

StAR:

steroidogenic acute regulatory protein

TIF-2:

transcription intermediary factor 2

TCF:

T-cell factor

Wnt4:

Wingless-Int signaling pathway gene 4

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia

    A. S. Orekhova & P. M. Rubtsov

  2. Moscow Institute of Physics and Technology, State University, Dolgoprudny, Moscow region, 141700, Russia

    P. M. Rubtsov

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  1. A. S. Orekhova
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Correspondence to P. M. Rubtsov.

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Original Russian Text © A.S. Orekhova, P.M. Rubtsov, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 1, pp. 75–88.

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Orekhova, A.S., Rubtsov, P.M. DAX1, an unusual member of the nuclear receptor superfamily with diverse functions. Mol Biol 49, 65–76 (2015). https://doi.org/10.1134/S0026893315010124

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