Downregulation of RAR alpha in mice by antisense transgene leads to a
compensatory increase in RAR beta and RAR gamma and development of lymphoma
T Manshouri, Y Yang, H Lin, SA Stass, AB Glassman, MJ Keating and M Albitar
Division of Laboratory Medicine, The University of Texas M.D. Anderson
Cancer Center, Houston 77030-4095, USA.
Retinoic acid receptors (RARs) alpha, beta, and gamma contain retinoic acid
response elements (RAREs) in their promoter regions and respond to their
own activation, thus forming an autoregulatory loop. We generated
transgenic mice that expressed an antisense construct of the RAR alpha.
Homozygous transgenic mice demonstrated 30% to 80% reduction in RAR alpha
protein expression in various tissues. Unlike RAR alpha null mice generated
by knockout, our antisense mice demonstrated significant compensatory
increases in the expression of RAR beta and RAR gamma proteins. Coarse fur,
male sterility, and low body weight were other abnormalities observed in
these mice. Most importantly, lymphoma developed in 44% of our homozygous
transgenic mice at an early stage of life. These data suggest that RAR
alpha is necessary for appropriate response of the RAR beta and RAR gamma
genes to physiologic changes and deregulation of the RAR alpha in
transgenic mice, which resulted in upregulation of RAR beta and RAR gamma,
can be associated with lymphomagenesis. Thus, the data support the
hypothesis that a balance among the RARs is necessary for appropriate
response to various homeostatic needs.
Volume 89,
Issue 7,
pp. 2507-2515,
04/01/1997
Copyright © 1997 by The American Society of Hematology
