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Function and regulation of myc-family bHLHZip transcription factors during the animal and plant cell cycle

Su, Yingtao (2008). Function and regulation of myc-family bHLHZip transcription factors during the animal and plant cell cycle. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2008:36
ISBN 978-91-85913-69-5
[Doctoral thesis]

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Abstract

The myc-family of proto-oncogenes (c-, N- and L-myc) encodes transcription factors of the basic region helix-loop-helix leucine zipper (bHLHZip) family and plays important roles in cell proliferation, metabolism, apoptosis and many other fundamental cellular processes. myc-family genes are frequently deregulated in cancer, often correlating with poor prognosis. c-Myc is estimated to regulate 15% of all genes. This thesis focuses firstly on the mechanisms behind posttranslational negative regulation of Myc activities induced by growth inhibitory signals, secondly on the regulation of transcription of genes involved in G1/S transition during cell cycle by Myc, and thirdly on characterization of myc-related bHLH genes in Arabidopsis. Our results show that the cytokine interferon (IFN)-γ induces ubiquitylation and degradation of Myc-family proteins in N-myc-amplified neuroblastoma cells and in Myc-transformed monocytic cells and induces expression of the Myc antagonist Mad1. IFN-γ-induced turnover of Myc involves reduced phosphorylation of Ser-62 through inhibition of cyclin E/ cyclin-dependent kinase 2 (Cdk2), which was identified as a Ser-62 kinase. The mechanism behind this inhibition was shown to be IFN-γ-induced expression of the Cdk-inhibitor p27Kip1. p27Kip1 was further demonstrated to target the Myc/cyclin E/Cdk2-complex directly at Myc target promoters, resulting in transcriptional repression of Myc target genes. This study also shows that during cell cycle progression, Myc associates with S-phase genes already in early G1 but cannot activate those genes until in late G1/S. This correlated with binding of the E3 ubiquitin ligase and cofactor Skp2 to these promoters. We propose that Skp2 and cyclin E/Cdk2 cooperate in this regulation. Taken together, this thesis suggests that Myc intimately interact with cyclinE/Cdk2, p27Kip1, and Skp2 in the control of the cell cycle genes, which might provide potential new strategies for cancer therapy. Our study in the plant Arabidopsis thaliana (At)characterized 84 myc-related At bHLH genes. Expression profiling of these genes in proliferative tissues showed that 15 of the bHLH genes were expressed in a cell cycle regulated manner, suggesting that they may play a role in cell division in plants.

Authors/Creators:Su, Yingtao
Title:Function and regulation of myc-family bHLHZip transcription factors during the animal and plant cell cycle
Year of publishing :2008
Volume:2008:36
Number of Pages:106
Papers/manuscripts:
NumberReferences
ALLI Cetinkaya, C., Hultquist, A., Su, Y., Wu, S., Bahram, F., Påhlman, S., Guzhova, I., Larsson, L.G. (2007) Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells. Mol Cancer Ther. 6, 2634-41. II Bahram, F., Su, Y., Hydbring, P., von der Lehr, N, Lilischkis, R., Fahlén, S, Hein, N., Henriksson, M. A., Wu, S., Vervoorts, J, Lüscher, B., and Larsson1, L.G. Interferon-gamma represses Myc function via p27Kip1 by inhibiting cyclin E/Cdk2-mediated phosphorylation of Ser62. Manuscript III Su, Y., Nilsson, H., von der Lehr, N., Tronnersjö1, S., Larsson, L.G. Specific requirements for activation of late G1/S phase genes by c-Myc -potential coactivating roles of cyclin E/Cdk2 and Skp2. Manuscript. IV Su, Y., Bako, L., Ellerström, M., Wu, S., Ezcurra1, I., Sundberg, E., and Larsson, L.G. Characterization of cell cycle regulated bHLHZip genes in Arabidopsis thaliana. Manuscript.
Place of Publication:Uppsala
ISBN for printed version:978-91-85913-69-5
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agrovoc terms:cell cycle, genes, transcription, transcription factors, neoplasms, arabidopsis thaliana
Keywords:Myc, Mad1, interferon-γ, cyclin E/Cdk2, p27Kip1, Skp2, transcription, cell cycle, bHLH, Arabidopsis thaliana
URN:NBN:urn:nbn:se:slu:epsilon-2212
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-2212
ID Code:1752
Department:(NL, NJ) > Dept. of Plant Biology and Forest Genetics (until 131231)
Deposited By: Yingtao Su
Deposited On:06 May 2008 00:00
Metadata Last Modified:02 Dec 2014 10:13

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