Abnormal Proliferation

 Cells have special genes called tumor suppressor genes that can neutralize the effect of harmful genetic alterations and prevent uncontrolled cell proliferation.

For example, p53 is a tumor suppressor gene that maintains a basal level of expression under normal cell conditions.

Mdm2 protein acts as a negative regulator of p53 activity. It binds to the functional domain of p53 protein, reducing its transcriptional activity.

Mdm2 also exhibits p53-specific ubiquitin ligase activity and catalyzes the attachment of ubiquitin to p53. The polyubiquitinated p53 proteins are then recognized and degraded by the proteasome, maintaining it at extremely low levels inside the cell.

However, when the cells encounter abnormal conditions such as cellular stress or excessive mitogenic stimulation, the p53 gene is induced to enforce its tumor suppression activity.

For instance, overexpression of transcription factor Myc in the nucleolus triggers the accumulation of a tumor suppressor protein called- Arf.

Arf directly binds to Mdm2, inhibiting its ubiquitin ligase activity and sequestering it in the nucleolus, thus releasing active p53 into the nucleoplasm.

Active p53 then binds to specific DNA sequences and induces the expression of its target genes that can trigger accelerated DNA repair, arrest cell cycle, or induce cell apoptosis, thus, preventing further propagation of damaged cells.

 However, when genetic or epigenetic changes alter p53 activity, it results in the collapse of the cell’s protective mechanisms. Such cells start proliferating aggressively and form tumors.

Besides, overexpression of Mdm2 is also frequently observed in liposarcomas.  Although such tumors retain the normal p53 gene, the increased levels of Mdm2 keep p53 in an inactive state, hence, restricting their tumor suppression activity.