Academic Background

Role of MdmX in Cell Transformation and Tumorigenesis

MdmX is p53-binding proteins that functions as critical negative regulator of p53 activity in embryonic and adult tissue. Embryonic lethality caused by the loss of MdmX is completely rescued in p53-null background. Overexpression of MdmX was reported to inhibit p53 tumor suppressor functions in vitro, and amplification of MdmX is observed in variety of human cancers retaining wildtype p53. In contrast to the proposed oncogenic ability of overexpressed MdmX in p53 wildtype background, we found that MdmX suppresses tumorigenesis in mice deleted for p53 (Matijasevic, Steinman et al., 2008; Matijasevic et al., 2008). Loss of MdmX increases proliferation and spontaneous transformation of hyperploid p53-null cells in vitro. Increased proliferation correlates with reduction in chromosome number and with elevated multipolar mitotic spindle formation (see image) in both mouse embryonic fibroblasts and tumor cells. We now investigate molecular mechanisms involved in MdmX-mediated centrosome clustering that facilitates bipolar mitosis and its role in suppression of proliferation and tumorigenesis

Cellular Responses to Hypothermia

Mild hypothermia (28°C) increases the levels of tumor suppressor p53 protein in human fibroblasts and causes a p53-dependent cell cycle arrest in mouse fibroblasts; (Matijasevic et al., 1998). These findings suggest two areas of hypothermia application, cancer treatment and protection from environmental carcinogens.

Hypothermia and Cancer Treatment

Since many human tumors lack wild type p53 function, hypothermia may provide conditions for selective targeting of tumor cells; cell cycle arrest of normal cells at low temperature may protect them from cytotoxicity of drugs that target proliferating cells. Indeed, we found that, in contrast to p53-deficient cells, p53 wildtype cells survive much higher doses of drug 5-fluorouracil when incubated at 28°C than at 37°C (Matijasevic, 2002). Therefore, hypothermia may improve the therapeutic index of chemotherapy by the mechanisms based on the differences in cell cycle regulation between normal and tumor cells.

Hypothermia and DNA Damage/Repair

Acute and delayed toxicities from exposure to DNA-damaging agents such as sulfur mustard (SM) can be prevented or diminished by the activities of cellular DNA repair processes. At least two DNA repair mechanisms act upon SM-damaged DNA: base excision repair (BER) (Matijasevic et al., 1996) and nucleotide excision repair (NER) (Matijasevic et al., 2001). Surprisingly, activity of the first enzyme on BER pathway, DNA glycosylase, sensitizes cells to mustards (Matijasevic and Volkert, 2007). Low temperature improves recovery after the exposure to SM and the main component of this hypothermia-induced protection appears to be the inhibition of glycosylase activity.

Figure

MdmX prevents formation of multipolar spindles in p53-null cells.