Lyl1 interacts with CREB1 and alters expression of CREB1 target genes.
The basic helix-loop-helix (bHLH) transcription factor family contains key regulators of cellular proliferation and differentiation as well as the suspected oncoproteins Tal1 and Lyl1. Tal1 and Lyl1 are aberrantly over-expressed in leukemia as a result of chromosomal translocations, or other genetic or epigenetic events. Protein-protein and protein-DNA interactions described so far are mediated by their highly homologous bHLH domains, while little is known about the function of other protein domains. Hetero-dimers of Tal1 and Lyl1 with E2A or HEB, decrease the rate of E2A or HEB homo-dimer formation and are poor activators of transcription. In vitro, these hetero-dimers also recognize different binding sites from homo-dimer complexes, which may also lead to inappropriate activation or repression of promoters in vivo. Both mechanisms are thought to contribute to the oncogenic potential of Tal1 and Lyl1. Despite their bHLH structural similarity, accumulating evidence suggests that Tal1 and Lyl1 target different genes. This raises the possibility that domains flanking the bHLH region, which are distinct in the two proteins, may participate in target recognition. Here we report that CREB1, a widely-expressed transcription factor and a suspected oncogene in acute myelogenous leukemia (AML) was identified as a binding partner for Lyl1 but not for Tal1. The interaction between Lyl1 and CREB1 involves the N terminal domain of Lyl1 and the Q2 and KID domains of CREB1. The histone acetyl-transferases p300 and CBP are recruited to these complexes in the absence of CREB1 Ser 133 phosphorylation. In the Id1 promoter, Lyl1 complexes direct transcriptional activation. We also found that in addition to Id1, over-expressed Lyl1 can activate other CREB1 target promoters such as Id3, cyclin D3, Brca1, Btg2 and Egr1. Moreover, approximately 50% of all gene promoters identified by ChIP-chip experiments were jointly occupied by CREB1 and Lyl1, further strengthening the association of Lyl1 with Cre binding sites. Given the newly recognized importance of CREB1 in AML, the ability of Lyl1 to modulate promoter responses to CREB1 suggests that it plays a role in the malignant phenotype by occupying different promoters than Tal1.
San-Marina
Serban
S
Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue 9-111, Toronto, Ontario, Canada M5G 2M9.
Han
Youqi
Y
Suarez Saiz
Fernando
F
Trus
Michael R
MR
Minden
Mark D
MD
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism* / Q000502:physiology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism* / Q000502:physiology; D004247:DNA / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA; D050881:E1A-Associated p300 Protein; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; C115163:CREB1 protein, human; C497453:ID1 protein, human; C086541:LYL1 protein, human; C075640:ID3 protein, human; C494360:EP300 protein, human