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Control of growth and differentiation of human neuronal and hematopoietic tumour cells via Myc/Max/Mad-network proteins

Cetinkaya, Cihan (2005). Control of growth and differentiation of human neuronal and hematopoietic tumour cells via Myc/Max/Mad-network proteins. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis Agriculturae Sueciae, 1652-6880 ; 2005:22
ISBN 91-576-7021-8
[Doctoral thesis]

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The Myc/Max/Mad transcription factor network regulates a large number of genes involved in cell growth, differentiation and apoptosis. Myc activates and Mad represses and overlapping set of growth-promoting genes, and the network therefore seems to act as a molecular switch between growth and differentiation. Deregulation of myc–family genes occurs frequently in human cancers and is often associated with poor prognosis. One aim of this thesis was to identify negative growth signals affecting the expression and/or activity of N-Myc- and Mad-family in neuroblastomas. Our results show that Mad1 was upregulated during phorbol ester (TPA)-induced neuronal differentiation of SH-SY5Y human neuroblastoma cells lacking N-myc amplification, whereas this response was largely inhibited in N-myc-amplified neuroblastoma cells. However, interferon-γ (IFN-γ) in combination with retinoic acid (RA) or TPA strongly enhanced differentiation and growth arrest in the latter. This was accompanied by reduced N-Myc and/or upregulated Mad1 expression, resulting in changed occupancy at the ODC target gene promoter in vivo towards Mad1/Max predominance, and repression of N-Myc/Mad1 target genes. This suggests that combined RA+IFN-γ “differentiation therapy” may potentially be of clinical interest in neuroblastoma treatment. Addressing the role of Mad1 during hematopoietic differentiation, we show that enforced Mad1 expression in U-937 monoblasts by an inducible expression system led to inhibited cell growth and proliferation. However, Mad1 did not induce or enhance differentiation in the absence or presence of differentiation signals. Surprisingly, Mad1 stimulated TNF-α-, but not Fas-induced apoptosis in U-937 cells. Finally, addressing the still unclear mechanism by which c-Myc represses transcription, our results showed that differentiation-induced transcription of the cyclin-dependent kinase inhibitor p21Cip1 gene was repressed by c-Myc through interaction with the Zn-finger protein Miz-1 in vivo at the p21 core promoter. c-Myc seems to switch Miz-1 function from an activator to a repressor, thereby inhibiting cell cycle exit and differentiation.

Authors/Creators:Cetinkaya, Cihan
Title:Control of growth and differentiation of human neuronal and hematopoietic tumour cells via Myc/Max/Mad-network proteins
Series Name/Journal:Acta Universitatis Agriculturae Sueciae
Year of publishing :2005
Number of Pages:70
ALL1. Guzhova, I., Hultquist, A., Cetinkaya, C., Nilsson, K., Påhlman, S & Larsson, L.G. Interferon-γ cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition in human neuroblastoma cells. Int. J. Cancer 94, 97-108, 2001. 2. Cetinkaya, C., Hultquist, A., Wu, S., Guzhova, I., Påhlman, S. & Larsson, L.G. IFN-γ-stimulated terminal neuronal differentiation and growth arrest of N-myc amplified neuroblastoma cells involves repression of N-Myc target genes via upregulated Mad1. Manuscript. 3. Hultquist, A., Cetinkaya C., Wu, S., Castell, A., Erlandsson, A. & Larsson, L.-G. Mad1 inhibits cell growth and proliferation but does not promote differentiation or overall survival in human U-937 monoblasts. Mol. Cancer Res. 2, 464-476, 2004. 4. Wu S, Cetinkaya C, Munoz MJ, von der Lehr N, Bahram F, Beuger V, Eilers M, Leon J and Larsson LG. Myc represses differentiation-induced p21Cip1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 22, 351-360, 2003
Place of Publication:Uppsala
ISBN for printed version:91-576-7021-8
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X30 Life sciences
Subjects:Not in use, please see Agris categories
Agrovoc terms:cells, growth, cell differentiation, neoplasms, interferons
Keywords:Myc, Mad1, Miz-1, p21Cip1, Interferon-γ, retinoic acid, phorbol ester, differentiation, neuroblastoma, hematopoiesis
Permanent URL:
ID Code:774
Department:(NL, NJ) > Dept. of Plant Biology and Forest Genetics (until 131231)
Deposited By: Cihan Cetinkaya
Deposited On:25 Feb 2005 00:00
Metadata Last Modified:02 Dec 2014 10:07

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