Dr Helen Rizos

• Research Interests
• Publications
• Contact Details

Dr Helen Rizos heads the Cell Cycle Research Group which is part of the Westmead Institute for Cancer Research.

Research Interests

In Australia, melanoma is the third most common cancer in men and women with over 3,000 cases per year and an overall lifetime risk of 3.7%. We know now that cancer is caused by genetic changes, or mutations, in cells. However, the precise sequence of mutations required to transform a dormant melanocyte into a melanoma remains unresolved. In recent years our work has contributed to the identification of several critical pathways crucial to this process. In particular, the p16INK4a/p14ARF locus, which encodes the tumour suppressor proteins p16INK4a and p14ARF, is altered in 39% of melanoma-prone families and a single base change that activates the BRAF oncogene is found in 50-70% of melanomas. The Cell Cycle Research Group is investigating how these proteins work and which cellular targets they interact with.

This team recently proposed that the p14ARF protein mediates the attachment of the small modifying protein, SUMO, to a number of target proteins in a process called sumoylation. Sumoylation regulates cellular activity of these target proteins by altering their function. We are exploring the effects of p14ARF-induced sumoylation, and the consequences of p14ARF mutation on the functioning of these proteins .

Some studies have reported that p14ARF can induce programmed cell death, known as apoptosis, possibly by activating the master apoptosis gene p53. The Cell Cycle group has clarified that p14ARF induces apoptosis only when co-expressed at normal physiological levels in cells with a functional p53 gene; it cannot induce apoptosis by itself. p14ARF is also known to stabilize proteins such as p53 by blocking the attachment of the small modifier protein ubiquitination which acts as a degradation signal. The effect of melanoma associated p14ARF mutations on the degradation of essential proteins is also being investigated.

The p16INK4a tumour suppressor is frequently altered in high risk melanoma families, and these altered p16INK4a proteins may affect the function of the remaining normal copy of p16INK4a. This important hypothesis is currently being investigated by the Cell Cycle group and has important implications for determining the risk of developing melanoma and possibly the treatment strategy for patients carrying altered copies of the p16INK4a protein. Furthermore, it is likely that unidentified p16INK4a functions (other then regulation of cell proliferation) may add to its role as melanoma susceptibility gene. The Cell Cycle research group is investigating the role of p16INK4a in novel biomolecular pathways.

TheBRAF oncogene is switched on in most melanomas but intriguingly also in 80% of benign moles. Most moles never transform into melanomas and their melanocytes are normally growth arrested . Thus, although aberrant activation of BRAF plays a role in melanoma, normal melanocytes apparently respond to active BRAF by growth arrest and only additional genetic alterations allow these cells to become malignant. The Cell Cycle research group is exploring the mechanisms responsible for this BRAF-induced growth arrest, which is clearly critical in protecting against melanoma formation. These investigations will also resolve the molecular events necessary to transform a normal melanocyte into a melanoma.

Melanoma cancers are notoriously resistant to chemotherapy. Through its research, the Cell Cycle team has confirmed that cells in which p14ARF and p16INK4a are active are more sensitive to chemotherapy. The impact of activated BRAF on chemosensitivity is currently being investigated. All these molecules are critical in the genesis of melanoma. Therefore defining each of their functions is essential to the development of a rational approach to targeted therapy for this destructive disease.

For more information click here to visit the Cell Cycle website.

Publications

- 2007 - 2006 - 2005 -

2007

• Rizos H, Scurr LL, Irvine M, Alling NJ, Kefford RF. p14ARF regulates E2F-1 ubiquitination and degradation via a p53-dependent mechanism. Cell Cycle. 2007 May;6(14):1741-7 [Abstract]
• Packer LM, Pavey SJ, Boyle GM, Stark MS, Ayub AL, Rizos H, Hayward NK. Gene expression profiling in melanoma identifies novel downstream effectors of p14ARF. Int J Cancer. 2007 Aug 15;121(4):784-90. PMID: 17450523 [Abstract]

2006

• Rizos, H, McKenzie, H, Ayub, A, Woodruff, S, Becker, T, Scurr, L, Stahl, J, Kefford, R. Physical and functional interaction of the p14ARF tumor suppressor with ribosomes. The Journal of biological chemistry. 2006; 281:38080-8 [Abstract]

• Gallagher, S, Kefford, R, Rizos, H. The ARF tumour suppressor. The international journal of biochemistry & cell biology. 2006; 38:1637-41 [Abstract]

2005

• Becker, T, Ayub, A, Kefford, R, Mann, G, Rizos, H. The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired. International journal of cancer. Journal international du cancer. 2005; 117:569-73 [Abstract]

• Becker, T, Rizos, H, de la Pena, A, Leclercq, I, Woodruff, S, Kefford, R, Mann, G. Impaired inhibition of NF-kappaB activity by melanoma-associated p16INK4a mutations. Biochemical and biophysical research communications. 2005; 332:873-9 [Abstract]

• Rizos, H, Woodruff, S, Kefford, R. p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the Sumoylation of its binding partners. Cell cycle (Georgetown, Tex.). 2005; 4:597-603 [Abstract]

• Gallagher, S, Kefford, R, Rizos, H. Enforced expression of p14ARF induces p53-dependent cell cycle arrest but not apoptosis. Cell cycle (Georgetown, Tex.). 2005; 4:465-72 [Abstract]

Contact Details

T +61 2 9845 9059

F +61 2 9845 9102

E helen_rizos@wmi.usyd.edu.au