Avian erythroleukemia: a model for corepressor function in cancer.
Transcriptional regulation at the level of chromatin plays crucial roles during eukaryotic development and differentiation. A plethora of studies revealed that the acetylation status of histones is controlled by multi-protein complexes containing (de)acetylase activities. In the current model, histone deacetylases and acetyltransferases are recruited to chromatin by DNA-bound repressors and activators, respectively. Shifting the balance between deacetylation, i.e. repressive chromatin and acetylation, i.e. active chromatin can lead to aberrant gene transcription and cancer. In human acute promyelocytic leukemia (APL) and avian erythroleukemia (AEL), chromosomal translocations and/or mutations in nuclear hormone receptors, RARalpha [NR1B1] and TRalpha [NR1A1], yielded oncoproteins that deregulate transcription and alter chromatin structure. The oncogenic receptors are locked in their 'off' mode thereby constitutively repressing transcription of genes that are critical for differentiation of hematopoietic cells. AEL involves an oncogenic version of the chicken TRalpha, v-ErbA. Apart from repression by v-ErbA via recruitment of corepressor complexes, other repressors and corepressors appear to be involved in repression of v-ErbA target genes, such as carbonic anhydrase II (CAII). Reactivation of repressed genes in APL and AEL by chromatin modifying agents such as inhibitors of histone deacetylase or of methylation provides new therapeutic strategies in the treatment of acute myeloid leukemia.
Rietveld
L E
LE
Department of Molecular Biology, NCMLS, Geert Grooteplein Zuid 26, PO Box 9101 6500 HB Nijmegen, The Netherlands.
Caldenhoven
E
E
Stunnenberg
H G
HG
D001355:Alpharetrovirus; D000818:Animals; D001353:Avian Leukosis / Q000235:genetics* / Q000821:virology; D002645:Chickens; D005786:Gene Expression Regulation; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000821:virology; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology; D012192:Retroviridae Infections / Q000235:genetics* / Q000821:virology
D012097:Repressor Proteins