Suspected leukemia oncoproteins CREB1 and LYL1 regulate Op18/STMN1 expression

Stathmin (STMN1) is a microtubule destabilizing protein with a key role in cell cycle progression and cell migration that is up-regulated in several cancers and may contribute to the malignant phenotype. However, the factors that regulate its expression are not well understood. Loss as well as gain-of-function p53 mutations up-regulate STMN1 and in acute myelogenous leukemia where p53 is predominantly wild-type, STMN1 is also over-expressed. Here we show regulatory control of STMN1 expression by the leucine zipper transcription factor (TF) CREB1 and the basic helix-loop-helix TF LYL1. By ChIP-chip experiments we demonstrate in vivo the presence of LYL1 and CREB1 in close proximity on the STMN1 promoter and using promoter assays we reveal co-regulation of STMN1 by CREB1 and LYL1. By contrast, TAL1, another suspected oncoprotein in leukemia and close relative of LYL1, exerts no regulatory effect on the STMN1 promoter. NLI, LMO2 and GATA2 are previously described co-activators of Tal1/Lyl1-E47 transcriptional complexes and potentiate Lyl1 activation of the STMN1 promoter while having no effect on TAL1 transactivation. Promoter mutations that abrogate CREB1 proximal binding or mutations of the DNA-binding domain of CREB1 abolish LYL1 transcriptional activation. These results show that CRE and Ebox sites function as coordinated units and support previous evidence of joint CREB1-and LYL1 transcription events activating an aberrant subset of promoters in leukemia. CREB1 or LYL1 shRNA knock-down down-regulate STMN1 expression. Because down-regulation of STMN1 has been shown to have anti-proliferative effects, while CREB1 and LYL1 are suspected oncoproteins, interference with CREB1-LYL1 interactions may complement standard chemotherapy and yield additional beneficial effects.