Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.
The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.
Baek
Kwan-Hyuck
KH
Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA.
Zaslavsky
Alexander
A
Lynch
Ryan C
RC
Britt
Carmella
C
Okada
Yoshiaki
Y
Siarey
Richard J
RJ
Lensch
M William
MW
Park
In-Hyun
IH
Yoon
Sam S
SS
Minami
Takashi
T
Korenberg
Julie R
JR
Folkman
Judah
J
Daley
George Q
GQ
Aird
William C
WC
Galdzicki
Zygmunt
Z
Ryeom
Sandra
S
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002396:Catechols; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D007294:Inositol / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000097603:Dyrk Kinases
D019703:Calcineurin; D002135:Calcium-Binding Proteins; D002396:Catechols; D004268:DNA-Binding Proteins; D007294:Inositol; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C079348:Cancell; C511512:DSCR1 protein, mouse; C108612:RCAN1 protein, human