The MDM2 protein plays a significant role in cells, acting as a regulator that maintains cellular health and balance. This protein is a component of cellular machinery that ensures cells function correctly and respond to various internal and external signals. Its management of other proteins contributes to cellular stability.
MDM2’s Normal Cellular Function
Within healthy cells, MDM2 primarily functions as a negative regulator of the p53 tumor suppressor protein. The p53 protein is often referred to as the “guardian of the genome” because it prevents damaged cells from proliferating. When DNA damage or other cellular stresses occur, p53 can activate genes that halt cell division or trigger programmed cell death, known as apoptosis, eliminating compromised cells.
MDM2 controls p53 levels and activity by acting as an E3 ubiquitin ligase. This means MDM2 attaches small tags called ubiquitin to p53, marking it for destruction by the cell’s waste disposal system, the proteasome. This ubiquitination keeps p53 levels low in unstressed cells, preventing unnecessary activation of cell cycle arrest or apoptosis. MDM2 also inhibits p53’s ability to activate gene transcription by binding to its transactivation domain.
A balanced feedback loop between MDM2 and p53 maintains cellular stability. When p53 levels rise in response to stress, p53 can activate the gene that produces MDM2. The increased MDM2 then promotes the degradation of p53, bringing its levels back down once stress is resolved. This autoregulatory loop ensures p53 activity is tightly controlled, preventing excessive cell growth inhibition or cell death.
When MDM2 Goes Wrong in Cancer
Dysregulation or overexpression of MDM2 disrupts this delicate balance, inactivating p53 even when p53 itself is not mutated. MDM2 overexpression is common in various human cancers, including sarcomas, gliomas, and breast cancers. When MDM2 is overactive, it excessively degrades p53, allowing cells with damaged DNA to divide unchecked. This uncontrolled proliferation contributes significantly to tumor formation and progression.
Genetic amplification of the MDM2 gene is a primary mechanism for its overexpression in many tumors. This amplification increases MDM2 protein production, overwhelming the p53 tumor suppressor pathway. This leads to a loss of p53’s protective functions, such as inducing cell cycle arrest or apoptosis, promoting cancer development. In some cases, MDM2 overexpression occurs through mechanisms other than gene amplification, leading to p53 inactivation.
Beyond its interaction with p53, MDM2 can also contribute to cancer development through p53-independent roles. MDM2 can influence cell cycle control, differentiation, and DNA repair, even without functional p53. For example, MDM2 interacts with other tumor suppressor proteins like the retinoblastoma protein (pRb), affecting cell cycle progression independently of p53. MDM2 can also regulate genes involved in metabolic processes like serine metabolism, promoting tumor growth in a p53-independent manner.
Targeting MDM2 in Cancer Treatment
Understanding MDM2’s role in cancer has opened avenues for therapeutic interventions, especially in tumors where p53 is functional but suppressed by MDM2 overexpression. Targeting MDM2 aims to reactivate p53’s tumor-suppressing functions, inhibiting cancer cell growth and promoting their elimination. This strategy is attractive for approximately 50% of human cancers where p53 is not mutated but its function is compromised by high MDM2 levels.
A main approach involves developing small molecule inhibitors designed to disrupt the interaction between MDM2 and p53. These inhibitors, such as Nutlins and MI-219, bind to MDM2, preventing its interaction with p53. This unblocks p53, allowing it to accumulate and initiate its normal functions, such as inducing cell cycle arrest or apoptosis in tumor cells. Unlike traditional chemotherapy, these agents are “nongenotoxic” because they do not directly damage DNA.
Research explores MDM2 inhibitors as both single therapies and in combination with other cancer treatments. For instance, milademetan, an oral MDM2 inhibitor, has shown promising results in clinical trials for certain cancers like liposarcoma. These inhibitors reactivate p53 in tumor cells, leading to tumor shrinkage. MDM2 inhibition is an active area of drug development, with new compounds like BI 907828 and alrizomadlin being investigated for their potential to restore p53 activity and combat various solid tumors.