p53 negatively regulates expression of FOXM1
ABSTRACT The Forkhead box M1 (FoxM1) oncogenic transcription factor is overexpressed in a majority of human tumors. p53 is a transcription factor and a major tumor suppressor that is mutated in 50% of human cancers. In this study, we compared the levels of FoxM1 in normal BJ human fibroblasts, BJ fibroblasts with p53 knockdown and corresponding BJ immortal/oncogenic cell lines with inactivated p53. We found that partial deletion or inactivation of p53 in these cells leads to upregulation of FoxM1 expression. Similarly, p53 knockdown in several human cancer cell lines with wt-p53 led to upregulation of FoxM1 mRNA and protein expression, while induction of p53 by DNA-damage led to downregulation of FoxM1. These data suggest that p53 negatively regulates FoxM1 expression and therefore inactivation of p53 in tumors could partially explain the phenomenon of FoxM1 overexpression in human cancers.
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- "When we compared levels of FOXM1 in normal human fibroblasts, fibroblasts with p53 knockdown, and corresponding immortal/oncogenic cell lines with inactivated p53, we found that partial deletion or inactivation of p53 leads to upregulation of FOXM1 expression . Similarly, p53 knockdown in several human cancer cell lines with wild-type p53 led to upregulation of FOXM1 mRNA and protein expression, while induction of p53 by DNA damage led to downregulation of FOXM1. "
ABSTRACT: The oncogenic transcription factor FOXM1 is one of the key regulators of tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone nucleophosmin. We also determined that FOXM1 is negatively regulated by the tumor suppressor p53. We identified the thiazole antibiotics Siomycin A and thiostrepton as inhibitors of transcriptional activity and FOXM1 expression via proteasome inhibition. In addition, we found that all tested proteasome inhibitors target FOXM1. We showed synergy between thiostrepton and bortezomib in different human cancer cell lines and in vivo. We generated isogenic human cancer cell lines of different origin with wild-type p53 or p53 knockdown and we demonstrated that proteasome inhibitors induce p53-independent apoptosis in these cells. Using RNA-interference or proteasome inhibitors to inhibit FOXM1 we found that suppression of FOXM1 sensitized human cancer cells to apoptosis induced by DNA-damaging agents or oxidative stress. We encapsulated thiostrepton into micelle-nanoparticles and after injection we detected accumulation of nanoparticles in tumors and in the livers of treated mice. This treatment led to inhibition of human xenograft tumor growth in nude mice. Our data indicate that targeting FOXM1 increases apoptosis and inhibits tumor growth.06/2014; 2014:596528. DOI:10.1155/2014/596528
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- "FOXM1 is expressed in all replicating cells, but not in quiescent and terminally differentiated cells. FOXM1 is regulated by numerous oncogenic signals, growth factors, p53, pRb, p19ARF, and itself (by auto-regulation) [6,7,8,9,10,11]. As a transcription factor, FOXM1 targets and controls a variety of genes, including CTNNB1 [12,13,14] for adherens junctions and cell self-renewal, CDKN1A  for cell proliferation, VEGF  for blood vessel formation, MMP2  and JNK1  for cell migration, HELLS  and SKP2  for cell cycle regulation, and NR3A1  for estrogen signaling in humans by binding to promoter regions with a preference for a conserved consensus 5'-TAAACA-3' sequence. "
ABSTRACT: Transcription factor Forkhead Box Protein M1 (FOXM1) is a well-known master regulator in controlling cell-cycle pathways essential for DNA replication and mitosis, as well as cell proliferation. Among the three major isoforms of FOXM1, FOXM1B is highly associated with tumor growth and metastasis. The activities of FOXM1B are modulated by post-translational modifications (PTMs), such as phosphorylation, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of the current study was to determine whether FOXM1B is post-translationally modified by SUMO proteins and also to identify SUMOylation of FOXM1B on its target gene transcription activity. Here we report that FOXM1B is clearly defined as a SUMO target protein at the cellular levels. Moreover, a SUMOylation protease, SENP2, significantly decreased SUMOylation of FOXM1B. Notably, FOXM1B is selectively SUMOylated at lysine residue 463. While SUMOylation of FOXM1B is required for full repression of its target genes MiR-200b/c and p21, SUMOylation of FOXM1B is essential for full activation of JNK1 gene. Overall, we provide evidence that FOXM1B is post-translationally modified by SUMO and SUMOylation of FOXM1B plays a functional role in regulation of its target gene activities.International Journal of Molecular Sciences 06/2014; 15(6):10233-10251. DOI:10.3390/ijms150610233 · 2.86 Impact Factor
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- "The roles of p53 inducing cell cycle arrest rivals with Plk1 functions which promotes the progression of the cell cycle. Plk1 is inhibitied by ATM/ATR dependent fashion after DNA damage (11,44), and is transcriptionally regulated either directly or indirectly by p53 (62-64). It localizes to the Plk1 promoter and binds to E2F1 which induces an increment of transcriptional level of Plk1. "
ABSTRACT: Polo-like kinase-1 (Plk1) belongs to a family of serine-threonine kinases and plays a critical role in mitotic progression. Plk1 involves in initiation of mitosis, centrosome maturation, bipolar spindle formation, and cytokinesis, which are well-reported as traditional functions of Plk1. In this review, we discuss the role of Plk1 during DNA damage response beyond the functions in mitotsis. When DNA damage is occurred in cells under various stress conditions, the checkpoint mechanism is activated to allow cells to have enough time for repair. In damage is repaired, cells progress continuously their division, which is called checkpoint recovery. If damage is too severe to repair, cells undergo apoptotic pathway. Lastly, if damage is not completely repaired, cells undergo a process called checkpoint adaptation, and resume cell division cycle with damaged DNA. Plk1 targets and regulates many key factors in the process of damage response, and we deal with these subjects in this review.BMB reports 03/2014; 47(5). DOI:10.5483/BMBRep.2014.47.5.061 · 2.60 Impact Factor