ID1 and ID2 are retinoic acid responsive genes and induce a G0/G1 accumulation in acute promyelocytic leukemia cells.
Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA), which results in the expression of genes that induce the terminal granulocytic differentiation of the leukemic blasts. Here we report the identification of two ATRA responsive genes in APL cells, ID1 and ID2. These proteins act as antagonists of basic helix-loop-helix (bHLH) transcription factors. ATRA induced a rapid increase in ID1 and ID2, both in the APL cell line NB4 as well as in primary patient cells. In addition, a strong downregulation of E2A was observed. E2A acts as a general heterodimerization partner for many bHLH proteins that are involved in differentiation control in various tissues. The simultaneous upregulation of ID1 and ID2, and the downregulation of E2A suggest a role for bHLH proteins in the induction of differentiation of APL cells following ATRA treatment. To test the relevance of this upregulation, ID1 and ID2 were overexpressed in NB4 cells. Overexpression inhibited proliferation and induced a G0/G1 accumulation. These results indicate that ID1 and ID2 are important retinoic acid responsive genes in APL, and suggest that the inhibition of specific bHLH transcription factor complexes may play a role in the therapeutic effect of ATRA in APL.
Nigten
J
J
Central Hematology Laboratory and Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Breems-de Ridder
M C
MC
Erpelinck-Verschueren
C A J
CA
Nikoloski
G
G
van der Reijden
B A
BA
van Wageningen
S
S
van Hennik
P B
PB
de Witte
T
T
Löwenberg
B
B
Jansen
J H
JH
D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D012097:Repressor Proteins; D014157:Transcription Factors; D014212:Tretinoin; C497453:ID1 protein, human; C497450:ID2 protein, human; C407909:TCF3 protein, human