Last week I wrote about the possible contribution to renal tumourigenesis posed by inactivation (or deregulation) of DNA repair enzymes. Following on from that theme I found a paper by Komori et al, 2009* in Oncogene entitled ‘A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA’. In it, the authors theorise that the protein MAPO1 may participate in the signalling cascade downstream of the DNA repair protein MGMT.

MGMT is responsible for the detection and repair of DNA damage caused by alkylating agents. If the damage is severe enough then the repair mechanism is bypassed, and to prevent transition mutations being propagated after DNA replication, apoptosis is initiated by MGMT via MAPO1, as the authors suggest.

So how is this relevant to BHD Syndrome? MAPO1 also goes by the name FNIP2. The relationship between FNIP2 and FLCN is not fully understood but could FLCN have any role in regulating FNIP2 activity in apoptosis induction in response to alkylating damage? Could this facet contribute to the accumulation of genetic instability in tissues with high cell turnover and metabolism (i.e. the kidneys) and could we speculate that this could contribute to the development of malignant tumours in the kidneys of BHD patients as opposed to any other organ since the kidneys are exposed to high levels of external chemicals due to their role in filtering urine?

Komori, K., Takagi, Y., Sanada, M., Lim, T.-H., Nakatsu, Y., Tsuzuki, T., Sekiguchi, M., Hidaka, M. A novel protein, MAPO1, that functions in apoptosis triggered by O(6)-methylguanine mispair in DNA. Oncogene 28: 1142-1150, 2009.

www.bhdsyndrome.org – the primary online reference site for anyone intersted in BHD Syndrome.

The focus of scientific research into BHD Syndrome should centre on elucidating the biological role of folliculin (FLCN) within the cell, but a recent paper in the European Journal of Cancer has brought the topic of DNA repair enzymes into light.

The multi-step model for tumourigenesis proposes that the tumourigenic growth of malignant cells from normal tissue is preceded by the accumulation of genetic errors in a sequential fashion, where each step provides a positive growth advantage to the nascent tumour cells, allowing them to break free from the normal regulatory constraints that determine normal growth and differentiation. Habib et al, (2010)* have shown that rapamycin treated HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells leads to increased protein and promoter activity of the DNA repair enzyme OGG1 and that this mediated via an increase in  expression of the transcription factor, NF-YA. This increase in OGG1 activity is thought to suppress the development of further tumours in treated cells and the authors speculate that a rapamycin-mediated mechanism of enhancing DNA repair in cancer cells  may explain the inhibition of further tumourigenic growth for as long as rapamycin is applied.

DNA repair enzymes such as OGG1 repair damage to DNA bases caused by oxidative damage, which may occur because of normal aerobic metabolism or exposure to external environmental carcinogens. Whilst such damage itself is not immediately pathogenic, it results in a mutator phenotype since the ‘increasing impairment in DNA repair contributes to the genomic instability, and consequently increases the risk of cancer’. Indeed, a familial colorectal polyposis syndrome know as MAP is  caused by bialleic inactivation of the DNA repair enzyme MUTYH, so as ‘family’ of proteins, their significance in cancer aetiology is not to be underestimated.

Given the phenotypic overlap between BHD Syndrome, VHL and TSC, as well as the role implicated for FLCN in mTOR signalling (and subsequent therapeutic benefit of rapamycin analogs) I wonder whether DNA repair enzymes may have a similar role in BHD associated tumourigenesis.

*Habib SL, et al. Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition.Eur J Cancer. 2010 Jul 23.

www.bhdsyndrome.org – the primary online reference site for anyone interested in BHD Syndrome.

Genomic and clinical studies make up the majority of published research into BHD Syndrome. Proteomics is the large scale analysis of proteins (or the ‘proteome’) and can be used to identify differential transcription of proteins and their biological activity. There are currently no proteomic based studies being performed in the field of BHD research.Would its implementation help further our knowledge of the disease and support ongoing studies? A Chinese group based at the Beijing Proteome Research Centre, China have used proteomic analysis to provide comprehensive functional annotation of proteins implicated in liver development and disease (Sun et al, 2010), could a similar project be used to identify the ins and outs of the BHD kidney?

Sun A et al, 2010. Liverbase: a comprehensive view of human liver biology. J Proteome Res. Jan;9(1):50-8.

www.bhdsyndrome.org – the primary online reference site for anyone interested in BHD Syndrome.

Makita et al, 2008 determined that TAZ is essential for developmental mechanisms involved in renal and pulmonary organogenesis and that its dysfunction may be a pathogenic mechanism in common human disease. Inactivation of TAZ in mice resulted in pathological changes in the kidney and lung that resemble the common human diseases polycystic kidney disease and pulmonary emphysema. After birth, only one-fifth of TAZ-deficient homozygotes grew to adulthood and demonstrated multicystic kidneys with severe urinary concentrating defects and polyuria. Furthermore, adult TAZ-deficient homozygotes exhibited diffuse emphysematous changes in the lung.

TAZ, a transcriptional co-activator with a PDZ-binding motif (also called WWTR1) is a 14-3-3-binding molecule. TAZ acts as a co-activator for several transcription factors as well as a modulator of membrane-associated PDZ domain-containing proteins, but its physiological roles remain unknown.

The coexistence of renal and pulmonary defects observed in TAZ-deficient mice hasn’t been observed before. TAZ may have a role in a pathway common to pulmonary and renal development and so further investigation could uncover a common mechanism for organogenesis and pathogenesis of human diseases. That said, is this phenotype limited to a single mouse model and due to the specific genetic background or could the similarities observed between this phenotype and BHD Syndrome suggest any mechanistic overlap between TAZ and FLCN?

www.BHDsyndrome.org – the primary reference site for anyone interested in BHD Syndrome

Makita R et al, 2008. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am J Physiol Renal Physiol. Mar; 294(3):F542-53.