Targeted expression of c-Myc in the epidermis alters normal proliferation, differentiation and UV-B induced apoptosis

Waikel, Rebekah L.; Wang, Xiaojing; Roop, Dennis R.

doi:10.1038/sj.onc.1203040

Cited by 72 publications

(67 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A parallel scenery has recently been described for promyelocytic leukemia, where TP53 mutation is absent and the oncogenic transcription factor PML-RARa impairs p53 transcriptional activity (Insinga et al, 2004). Apoptosis protection by c-Myc is not without precedent and has been observed in other models (Wu et al, 1996;Waikel et al, 1999;Liu et al, 2000;D'Agnano et al, 2001;Ebinuma et al, 2001). However, our results argue for a novel pathway for cMyc impairment of p53-mediated apoptosis.…”

Section: Myc and P53 Antagonism: Implications In Tumorigenesiscontrasting

confidence: 53%

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

et al. 2005

View full text Add to dashboard Cite

We have previously demonstrated that c-Myc impairs p53-mediated apoptosis in K562 human leukemia cells, which lack ARF. To investigate the mechanisms by which c-Myc protects from p53-mediated apoptosis, we used K562 cells that conditionally express c-Myc and harbor a temperature-sensitive allele of p53. Gene expression profiles of cells expressing wild-type conformation p53 in the presence of either uninduced or induced c-Myc were analysed by cDNA microarrays. The results show that multiple p53 target genes are downregulated when c-Myc is present, including p21 WAF1 , MDM2, PERP, NOXA, GADD45, DDB2, PIR121 and p53R2. Also, a number of genes that are upregulated by c-Myc in cells expressing wild-type conformation p53 encode chaperones related to cell death protection as HSP105, HSP90 and HSP27. Both downregulation of p53 target genes and upregulation of chaperones could explain the inhibition of apoptosis observed in K562 cells with ectopic c-Myc. Myc-mediated impairment of p53 transactivation was not restricted to K562 cells, but it was reproduced in a panel of human cancer cell lines derived from different tissues. Our data suggest that elevated levels of Myc counteract p53 activity in human tumor cells that lack ARF. This mechanism could contribute to explain the c-Myc deregulation frequently found in cancer.

show abstract

Section: Myc and P53 Antagonism: Implications In Tumorigenesiscontrasting

confidence: 53%

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

et al. 2005

View full text Add to dashboard Cite

show abstract

“…However, c-Myc does not confer an unspeci®c antiapoptotic e ect on K562 cells, as it does not protect from other apoptotic stimuli as okadaic acid or ceramides (CanÄ elles et al, 1997; our unpublished results). The antiapoptotic e ect of c-Myc has also been described in lymphoid cells (Sonenshein, 1997;Felsher and Bishop, 1999) and keratinocytes (Waikel et al, 1999), but its relationship with p53 function in these processes is unknown.…”

Section: Discussionmentioning

confidence: 99%

c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells

et al. 2000

View full text Add to dashboard Cite

c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two di erent methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53 Vall35 mutant, which adopts a wild-type conformation at 328C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc signi®cantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21 WAF1 , Bax and cytomegalovirus promoters. The impairment of p21 WAF1 transactivation by c-Myc was con®rmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21 WAF1 mRNA protein were signi®cantly reduced by cMyc, while Bax levels were una ected. Consistently, cMyc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation. These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for the frequently observed deregulation of c-myc in human cancer.

show abstract

“…This may be su cient to commit these cells to subsequent di erentiation, when c-Myc activity would no longer be required (see Gandarillas and Watt, 1997). Interestingly, constitutive activity of cMyc in mouse transgenic epidermis provoked hyperproliferation and hyperkeratosis (thickening of di erentiating layers), occasional nuclear division in di erentiating cells and angiogenesis, but not apoptosis (Pelengaris et al, 1999;Waikel et al, 1999). Mitogenic soluble factors produced in vivo during vascularisation, in¯ammation or tumorigenesis may favour mycinduced proliferation by alleviating the mitosis blockade.…”

Section: Mechanisms Of Keratinocyte Endoreplication and C-myc Functionmentioning

confidence: 99%

Normal and c-Myc-promoted human keratinocyte differentiation both occur via a novel cell cycle involving cellular growth and endoreplication

2000

View full text Add to dashboard Cite

The relationship between cell cycle and di erentiation in human keratinocytes is poorly understood. It is believed that keratinocytes suppress DNA replication and cell cycle arrest in G0 before they initiate terminal di erentiation. However, a temporal separation between both events has not been established. Moreover, c-Myc promotes keratinocyte di erentiation without causing cell cycle arrest. To address these paradoxes we have analysed cell cycle control during normal and c-Mycpromoted di erentiation. Continuous activation of c-Myc or initiation of terminal di erentiation results in a block of G2/M, cellular growth, endoreplication and polyploidy. Keratinocytes abandon G1, continue replicating DNA as they di erentiate terminally and become polyploid. In fact, simply blocking mitosis with nocodazole resulted in increased cell size, terminal di erentiation and endoreplication. This indicates that terminal di erentiation associates with defective cell cycle progression and provides a novel insight into c-Myc biology.

show abstract

Targeted expression of c-Myc in the epidermis alters normal proliferation, differentiation and UV-B induced apoptosis

Cited by 72 publications

References 49 publications

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells

Normal and c-Myc-promoted human keratinocyte differentiation both occur via a novel cell cycle involving cellular growth and endoreplication

Contact Info

Product

Resources

About