The transcription factor FOXM1c possesses a very strong C-terminal TAD (transactivation domain), but full-length FOXM1c is only a weak transactivator because the TAD is completely inhibited by the auto-inhibitory N-terminus. The N-terminus blocks the TAD by directly binding to the TAD. Accordingly, FOXM1c deletion mutants without N-terminus are strong transactivators. Therefore, the question arises whether signals exist, which activate full-length FOXM1c by releasing the FOXM1c-TAD from its inhibition by the N-terminus. Indeed, full-length FOXM1c is strongly activated by protein kinase CK2 and PKA (protein kinase A). Both CK2 and PKA do not activate a FOXM1c deletion mutant without N-terminus demonstrating that the activation of FOXM1c by CK2 and PKA depends on the presence of the IN-terminus. Consequently, CK2 and PKA activate FOXM1c by alleviating the inhibition of FOXM1c by its N-terminus. The presence of two potential CK2 phosphorylation sites and two potential PKA phosphorylation sites in the N-terminus of FOXM1c suggests that CK2 and PKA may activate FOXM1c through phosphorylation of the FOXM1c N-terminus. Thus, CK2 and PKA strongly activate full-length FOXM1c because they alleviate the repression of FOXM1c by its own auto-inhibitory N-terminus. Also c-Src activates full-length FOXM1c by relieving the inhibition of FOXM1c by its N-terminus. In contrast, Raf-1 activates FOXM1c independently of the FOXM1c N-terminus. In summary, this study shows for the first time that FOXM1c is activated by the four kinases CK2, PKA, c-Src and Raf-1. (C) 2011 Elsevier Inc. All rights reserved.