Retinoic acid as cause of cell proliferation or cell growth inhibition

Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors

George Wolf

Retinoic acid can combine with the nuclear retinoic acid receptor(RAR),leading to

cell growth inhibition,as in certain tumors.Retinoic acid can also bind to the orphan

nuclear receptor peroxisome proliferator-activated receptor b/d(PPAR b/d),

resulting in stimulation of cell growth and inhibition of apoptosis.To bind to RAR,

retinoic acid is carried into the nucleus by the cytosolic cellular retinoic acid-binding

protein-II;to bind to PPAR b/d,it is transported into the nucleus by the cytosolic fatty

acid-binding protein5.

©2008International Life Sciences Institute

INTRODUCTION

Textbooks on nutrition broadly describe vitamin A to function as a cofactor in the process of vision,as a hormone in reproduction,in embryonic development, bone growth,the immune system,the growth and differ-entiation of epithelia,and the inhibition of tumor growth. Clearly,stimulation of growth and differentiation of epi-thelia would have to occur by mechanisms different from inhibition of the growth of tumors.A recent report by Schug et al.1describes mechanisms whereby two such opposing activities can be performed by one vitamin.

Vitamin A,known as retinol,functions in the form of its metabolite,retinoic acid(RA),by binding to,and thus activating,its cognate nuclear hormone receptors RAR a, b,and g.In combination with the activated retinoic acid X receptor(RXR),a heterodimer is formed(RAR-RXR), which binds to specific target genes,leading to their trans-criptional expression,and ultimately to the regulation of their function.

The two opposing mechanisms taken as examples by Schug et al.1were1)the stimulation by RA of prolifera-tion of the basal keratinocytes of the skin and2)the well-known growth inhibition of cancer cells by RA.The first clues to a reconciliation of these opposing effects were obtained by Chapellier et al.2It appeared that in the skin of mice in which the normal RA receptors RAR a,b, and g were knocked out,RA-induced keratinocyte hyper-plasia still took place.The authors2found that the activa-tion by RA of a member of an entirely different family of nuclear receptors,the orphan receptor PPAR b/d,resulted in enhanced mitosis of cells of the basal layer of the kera-tinocytes of the skin,maintaining skin integrity and the epidermal barrier after wounding.3To follow up this finding,Shaw et al.4reported that,in fact,RA binds with high affinity to and activates PPAR b/d.Fluorescence titra-tion showed that PPAR b/d bound RA with K D=17nM, whereas PPAR a and g bound RA with K D=100–200nM. They found that,together with the co-activator SRC-1, binding of RA to PPAR b/d led to upregulation of the expression of3-phosphoinositide-dependent kinase1 (PDK1),a factor downstream of PPAR g/d,and subse-quently the activation of the anti-apoptotic factor Akt1.

The authors4thus were led to“the surprising conclu-sion”that RA can stimulate cell proliferation through binding to PPAR b/d and,as is well known,inhibit cell growth,as in cancer cells,by binding to RAR.The follow-ing question then arose:How can RA be partitioned between these two nuclear receptors,leading to two outcomes?

Affiliation:G Wolf is Adjunct Professor with the Department of Nutritional Sciences and Toxicology,University of California,Berkeley, California,USA.

Correspondence:G Wolf,c/o Editorial Office,Nutrition Reviews,International Life Sciences Institute,One Thomas Circle NW,Ninth Floor, Washington,DC20005,USA.E-mail:nutritionreviews@,Phone:+1-202-659-0074,Fax:+1-202-659-3859

Key words:cellular retinoic acid-binding protein-II,fatty acid-binding protein5,keratinocytes,mammary carcinoma MCF-7,peroxisome proliferator-activated receptor b/d,retinoic acid receptor

Emerging Science

doi:10.1111/j.1753-4887.2007.00006.x