HIGHLIGHTS EPIGENETICS analysis following digestion with a locus was not rearranged in any methylation-sensitive restriction of the 18 tumours tested. This was enzyme revealed that global methy- in contrast to Moloney murine lation levels were decreased. leukaemia virus (MMLV)-induced Less is more Interestingly, 80% of the mice devel- tumours, in which 3 of 12 tumours oped aggressive T-cell lymphomas at had an insertional rearrangement 4–8 months of age. These were in c-Myc. It was also thought Site-specific DNA hypermethylation shown to be monoclonal, which unlikely that the mechanism could is frequently implicated as a cancer- indicates that hypomethylation initi- be epigenetic, as hypomethylation causing mechanism, but what of ates cancer in a single cell that existed throughout development genome-wide hypomethylation, undergoes other events to become a and c-Myc was expressed at normal which also occurs in many human malignant tumour. levels in the thymuses of 2–4-week- tumours? Whether this is a cause or So how might hypomethylation old mice. consequence of cancer has long induce this lymphomagenesis? The However, there was already evi- been debated, but Rudolf Jaenisch authors proposed three possible dence that hypomethylation affected and colleagues, reporting in the 18 mechanisms: induction of endoge- genomic stability, and this was con- April issue of Science,have now nous retroviral elements could inser- firmed by carrying out array-based developed a mouse model to tionally activate proto-oncogenes; comparative genome hybridization. address this question. proto-oncogenes could be activated When hypomethylation-induced They generated viable, but small, by epigenetic effects; or genomic tumours were compared with mice that were compound heterozy- instability might be induced. MMLV-induced tumours, a signifi- gous for a hypomorphic allele and a The first possibility was ruled out cant increase in chromosome gains null allele of Dnmt1 — the DNA as retroviral element activation was — particularly of chromosome 15, methyltransferase that maintains not observed. c-Myc had already which contains c-Myc — was DNA methylation. These mice been found to be over-expressed in observed. Only 2 of 12 tumours did expressed just 10% of wild-type lev- most of the hypomethylation- not have this change, and these also els of the protein, and Southern blot induced T-cell lymphomas, but this had lower levels of c-Myc. TUMOUR SUPPRESSORS Unexpected relations Transforming growth factor (TGF)-β embryonic development, and that lack of p53 family members acted synergistically signalling induces a growth-arrest response in Xp53 caused abnormal development due to with the SMAD complex to activate normal cells. Cancer cells, however, frequently impaired TGFβ-induced gene responses. transcription from the SMAD-specific lose the ability to undergo TGF-β-mediated p53AS activated transcription of TGFβ promoter, Mix2.Several TGF-β target genes growth suppression, even without any genetic target genes in frog cells, by interacting with were found to be under joint control of p53 defects in the TGF-β signalling pathway. SMAD and acting as a sequence-specific and SMAD in mammalian cells. Stefano Piccolo and colleagues performed a transcription factor. So, is p53 involved in The ability of p53 to cooperate with screen to identify new modulators of the TGF-β signalling in human cancer cells? SMAD to control gene expression reveals a TGF-β response, and made the surprising The authors used small interfering RNAs new mechanism of regulating TGF-β discovery that p53 is involved in activation of (siRNAs) to reduce p53 levels in HepG2 cells signalling. p53 activity is disrupted in many TGF-β target genes. — a cancer cell line that is highly responsive tumour types, which might underlie their TGF-β family members bind to to TGFβ and that normally expresses p53. inability to undergo TGF-β-mediated serine/threonine kinase receptors and They found that reduction of endogenous growth inhibition. Further experiments are activate phosphorylation of the SMAD p53 levels reduced expression of TGF-β required to determine how p53/SMAD gene family of transcriptional regulators. SMADs target genes, and allowed cells to overcome targets block proliferation, and whether form a DNA binding complex with other the growth arrest that is normally imposed other p53 family members, such as p63 and cofactors to activate transcription of their by TGF-β signalling. Furthermore, restoring p73, can also modulate TGF-β signalling. target genes, but little is understood about p53 activity in a p53-null cancer cell line, Emma Croager other components that modify this which is normally insensitive to TGF-β signalling pathway. Piccolo and colleagues signalling, resulted in SMAD-dependent References and links ORIGINAL RESEARCH PAPER Cordenonsi, M. et al. Links performed an unbiased functional screen inhibition of cell growth. β β β between tumor suppressors: p53 is required for TGF- gene for activators of TGF- signalling during But how does p53 mediate the TGF- responses by cooperating with Smads. Cell 113, 301–314 embryonic development, and found that transcriptional response? The authors found (2003) one of these was a splice variant of p53 that p53 associates with SMAD2 and SMAD3 FURTHER READING Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000) (p53AS). They showed that p53AS activated in HepG2 cells, and that this association WEB SITE a subset of TGF-β target genes during frog depends on TGF-β signalling. Furthermore, Stefano Piccolo’s lab: http://www.bio.unipd.it/piccolo/ 392 | JUNE 2003 | VOLUME 3 www.nature.com/reviews/cancer © 2003 Nature Publishing Group.