What role do MDM2 and MDM4 proteins play in cells?

For more than 25 years, MDM2 and its homolog MDMX (also known as MDM4) have been shown to exert oncogenic activity. These two proteins are best understood as negative regulators of the p53 tumor suppressor, although they may have additional p53-independent roles.

What does Mdmx stand for?

In 1996, Shvarts et al. discovered a new binding protein of the tumor suppressor p53, which is highly homologous to a critical negative regulator of p53, i.e., the oncoprotein MDM2 (murine double minute 2) (1). Therefore, this new p53-associated protein was named MDMX (murine double minute X, also called MDM4) (1, 2).

What are the two roles of MDM2?

Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.

What is a key role of MDM2?

MDM2 is one of the most highly regulated proteins due to its significant role in modulating p53-dependent and -independent functions in various cancers [2]. In humans, the MDM2 gene was first isolated in 3T3DM cells from double minutes which are extrachromosomal amplified DNAs.

How do MDM2 inhibitors work?

MDM2 then inhibits the p53-mediated transcription of MDM2 and other downstream target genes by binding to p53, blocking its transactivation domain. Through E3 ubiquitin ligase activity, MDM2 promotes ubiquitination of p53, leading to increased p53 degradation.

What activates the p53 gene?

The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase ATM; recent results suggest ATM acts via the downstream kinase Chk2/hCds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20.

What inhibits MDM2?

RG7112. RG7112 was the first MDM2 inhibitor to be clinically assessed. Initial clinical assessment focused on MDM2-amplified liposarcoma [38]. In this study, RG7112 effectively inhibited p53–MDM2 binding to activate p53-mediated signaling, stimulate apoptosis, and prevent tumor growth [38].

What happens if p53 Cannot detect DNA damage?

This altered p53 protein cannot regulate cell growth and division and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. If such cells continue to divide in an uncontrolled way, they can lead to the formation of bladder cancer.

What does it mean to have melanoma in situ?

It means there are cancer cells in the top layer of skin (the epidermis). The melanoma cells are all contained in the area in which they started to develop and have not grown into deeper layers of the skin. Some doctors call in situ cancers pre cancer.

How is melanoma diagnosed in the TNM staging system?

In the TNM staging system melanoma in situ is the same as Tis, N0, M0. The stage of your cancer helps your doctor to decide what treatment you need. Treatment also depends on: Surgery is the main treatment. To diagnose melanoma doctors remove the abnormal area of skin and a small area of surrounding skin.

What does stage 0 melanoma on the skin mean?

Melanoma in situ is also called stage 0 melanoma. It means there are cancer cells in the top layer of skin (the epidermis).

How does a doctor diagnose and treat melanoma?

Surgery is the main treatment. To diagnose melanoma doctors remove the abnormal area of skin and a small area of surrounding skin. You may then need a second operation to remove a larger area of healthy tissue around where the melanoma in situ was. This is called a wide local excision.