EAPP, a Novel E2F Binding Protein That Modulates E2F-dependent Transcription

Novy, Michael; Pohn, Regina; Andorfer, Peter; Novy-Weiland, Tina; Galos, Barbara; Schwarzmayr, Ludwig; Rotheneder, Hans

doi:10.1091/mbc.e04-11-0975

Cited by 23 publications

(41 citation statements)

References 47 publications

(54 reference statements)

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“…We have shown previously that EAPP levels go down during mitosis. 21 Our model predicts that EAPP is required for Chk2 dephosphorylation. If it is correct, it could explain high Chk2 activity in mitosis.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 78%

“…We have previously identified EAPP (E2F-associated phosphoprotein) that stimulates E2F-dependent transcription and is found overexpressed in many human tumor cells. 21 This overexpression might be caused by aberrant ratios of the transcription factors Sp1, Sp3 and Egr-1, the main regulators of EAPP expression. 22 In a recently published study we could show that EAPP is influenced by DNA damage and is itself involved in the response to this damage.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

“…Chk2 mediated phosphorylation of Ser988 on BRCA1 and this is required for correct formation of EAPP is an E2F-binding protein that stimulates E2F-dependent transcription and is frequently overexpressed in human tumor cells. 21 We have shown recently that EAPP is not only essential for the survival of a cell but also an important regulator of p21 activity. 23 We show here that EAPP also interacts with Chk2 and seems to interfere with its activity.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

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EAPP modulates the activity of p21 and Chk2

2011

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Genomic instability is thought to be critical for the development of cancer. Among its causes microsatellite instability (MIN) and chromosomal instability (CIN) have attracted the most attention. Cell cycle checkpoints and DNA repair mechanisms are the first line of defense against DNA damage. Among the most dangerous DNA lesions are double-strand breaks. The response to DNA double strand breaks is regulated mainly by the serine/threonine kinases ATM and Chk2 and their downstream target the tumor suppressor p53, which in turn stimulates the expression of growth-inhibitory genes like CDKN1A (encoding p21) or proapoptotic genes like Bax. The balance between these gene products determines the fate of a cell. EAPP is a nuclear phosphoprotein that is frequently upregulated in human tumors. We have recently shown that EAPP levels are critical for cellular homeostasis. DNA damage elevates EAPP levels and its overexpression results in G 1 arrest and impairs apoptosis in a p21-dependent manner. EAPP binds to the p21 promoter, stimulates its activity and seems to be essential for transcription initiation.In the present work we show that EAPP also regulates the phosphorylation status and thus the activity of Chk2. EAPP binding seems to trigger the dephosphorylation of P-Chk2 resulting in its inactivation. A newly described function of Chk2 in mitosis that secures genomic integrity might also be affected by EAPP overexpression. This might explain the abundance of EAPP in aneuploid tumor cells.

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Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 78%

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

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EAPP modulates the activity of p21 and Chk2

2011

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“…This results in a significant increase of cell number, modulates the E2F-controlled transcription, stimulates proliferation and may be involved in the malignant transformation of cells. 70 The clone 3.12 offers similarity to the mRNA identified by the NCI-CGAP (http://www.ncbi.nlm.nih.gov/ncicgap) originating from human carcinoid lung tissue. Protein and gene functions are still unknown.…”

Section: Insert-comparison With Genomic Databasesmentioning

confidence: 99%

Induced and repressed genes after irradiation sensitizing by pentoxyphylline

Waldeck

Strunz

Müller

et al. 2006

Intl Journal of Cancer

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Aim in cancer therapy is to increase the therapeutic ratio eliminating the disease while minimizing toxicity to normal tissues. Radiation therapy is a main component in targeting cancer. Radiosensitizing agents like pentoxyphylline (PTX) have been evaluated to improve radiotherapy. Commonly, cells respond to radiation by the activation of specific early and late response genes as well as by inhibition of genes, which are expressed under normal conditions. A display of the genetic distinctions at the level of transcription is given here to characterize the molecular events underlying the radiosensitizing mechanisms. The method of suppression subtractive hybridization allows the visualization of both induced and repressed genes in irradiated cells compared with cells sensitized immediately after irradiation. The genes were isolated by cDNA-cloning, differential analysis and sequence similarity search. Genes involved in protein synthesis, metabolism, proteolysis and transcriptional regulation were detected. It is important that genes like KIAA280, which were only known as unidentified EST sequences before without function, but inaccessible by array technology were recovered as functional genes. Database searches for PTX-induced genes detected a human mRNA completely unknown. In case of suppressed genes, we detected several mRNAs; one thereof shows homology to a hypothetical protein possibly involved in signal transduction. A further mRNA encodes the protein BM036 supposed to associate with the E2F transcription factor. A hypothetical protein H41 was detected, which may repress the Her-2/neu receptor influencing breast cancer, gliomas and prostate tumors. Radiation combined with PTX may lead to a better prognosis by down regulation of the Her-2/neu, which will be proven by clinical studies in the near future. The connection between cancerogenesis and cyclins has been demonstrated with the aberrant expression of members of the family of cyclins and the mechanisms of the cell cycle G1 arrest and apoptosis were well documented. [3][4][5][6][7] The mechanisms of G2 arrest in contrast have been described to a lesser extent, although this event could be of relevance to the cellular survival after photonirradiation. 8,9 Beyond doubt, the G2-phase arrest is generally activated in response to DNA damage independent of the p53 status. 8 It acts as an universal feedback for maintaining the genomic integrity and for survival after irradiation by repairing DNA breaks prior to mitosis. 10 Much of the underlying knowledge on the G2/M phase was obtained by studying genes involved in the regulation of DNA damage response because DNA-damaging processes, like g-radiation, respond by arresting at cell cycle checkpoints. 11 This ''G2 delay'' after photon-irradiation involves molecular mechanisms like reduced cyclin B levels and inhibition of the Cdk1 activity. 8 Formation and activation of the maturation promoting factor (MPF) are pivotal for the G2/M checkpoint regulation. The transition from G2 into the mitosis occurs by the activatio...

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“…A yeast two-hybrid interaction www.intechopen.com screen with the amino-terminal region of E2F1 comprising the NLS but lacking the marked box led to the cloning of EAPP (E2F-associated phosphoprotein) (Novy et al 2005). EAPP appears to potentiate the proliferative functions of E2F1 in several ways.…”

Section: Genome-wide Yeast Two-hybrid Interaction Screeningmentioning

confidence: 99%