Regulation of gene expression in normal cells, aging cells and cancer cells;
Mechanisms of tumor suppression;
Functions of proteins encoded by endogenous retroviruses
Our current work focuses primarily on novel interactions between the p53 tumor suppressor and vitamin D pathways. Vitamin D receptor (VDR) and p53 are both transcription factors that exert important tumor suppressor functions. We have shown previously a crosstalk between these signaling pathways that involves binding of VDR to p53 and Murine Double Minute homologue 2 (MDM2). Our most recent findings suggest relevance of this interaction. Wildtype-p53 comes in two flavors, carrying either a proline (P) or arginine (R) at position 72, determined by single-nucleotide polymorphism rs1042522. With respect to tumor suppression, p53-72R is a bit stronger as it is a more efficient inducer of apoptosis in response to cellular stress. P53-72P, on the other hand, is associated with increased longevity in humans for unknown reasons not related to tumor suppression, and with reduced female fertility. Moreover, there is an intriguing shift in the ratio of the allele frequencies in dependence of latitude, with p53-72R being much more frequent in the North. One potential reason for this may have been recently identified by Maureen E. Murphy and colleagues: p53-72R can control fat metabolism to support obesity. We suggest another potential evolutionary reason for the increased p53-72R frequency in the North, related to the insufficiency of vitamin D production at Northern latitudes. Through initial in silico studies on public databases of p53-induced genes and qRT-PCR follow-ups, we identified and confirmed the gene CYP24A1 as significantly stronger activated in the presence of p53-72R (the Northern p53 variant) compared to p53-72P. CYP24A1 is not a directly p53-regulated gene but is regulated by the VDR in dependence of 1,25(OH)2D3 (active vitamin D). The presence of p53-72R permitted lower 1,25(OH)2D3 levels to achieve similar VDR activity (1,25(OH)2D3-dependent CYP24A1 transcript levels) as in the presence of p53-72P. The mechanisms that underlie the increased VDR activity in the presence of p53-72R are currently being worked out.
Another area of interest is the function of proteins encoded by human endogenous retroviruses (HERVs). Np9 (Nuclear protein of 9 kDa) identified by us (and shown by others to be expressed in induced pluripotent and embryonal stem cells), was recently demonstrated by us to be exclusively produced in gorilla, chimpanzee and human and to interact with MDM2 of the p53 tumor suppressor pathway. The precise functions of Np9 are unknown.