What is p53 independent apoptosis?

Apoptosis induced by p53 is firmly established as a central mechanism of tumour suppression. In addition to its complex functions as a nuclear transcription factor, p53 can act in the cytosol and mitochondria to promote apoptosis through transcription-independent mechan- isms.

What kind of protein is MDM2?

Using immunoprecipitation experiments with U937 cell lysates (leukemia cells), MDM2 was identified as an RB-binding protein. RB is a potent tumor suppressor that is mutated in different kinds of cancers. MDM2 inhibits the ability of RB to inhibit E2F1 function, thus inhibiting arrest of the cell cycle in G1 (69, 70).

What is the p53 independent pathway?

Our results showed that the p53 transcription-independent pathway represents the major part of the apoptotic response to high genotoxic stress. Thus, the transcription-independent action of p53 in genotoxic stress-induced apoptosis appears not to go through the same apoptosis mechanism in cytoplasm.

How does p53 promote apoptosis?

P53 induces apoptosis in nontransformed cells mostly by direct transcriptional activation of the pro-apoptotic BH3-only proteins PUMA and (to a lesser extent) NOXA. Combined loss of the p53 effectors of apoptosis (PUMA plus NOXA) and cell cycle arrest/cell senescence (p21) does not cause spontaneous tumour development.

What is the MDM2 gene?

The murine double minute 2 (mdm2) gene encodes a negative regulator of the p53 tumor suppressor. Amplification of mdm2 or increased expression by unknown mechanisms occurs in many tumors.

Why is the MDM2-p53 interaction important?

Disruption of the p53-MDM2 complex by multiple routes is the pivotal event for p53 activation, leading to p53 induction and its biological response. Because the p53-MDM2 interaction is structurally and biologically well understood, the design of small lipophilic molecules that disrupt or prevent it has become an important target for cancer therapy.

Where does Mdm2 transfer tags to p53?

MDM2 transfers monoubiquitin tags onto lysine residues mainly in the COOH terminus of p53 ( 21 –24 ). MDM2-mediated p53 ubiquitination takes place in the nucleus in a complex with the p300/CREB-binding protein (CBP) transcriptional coactivator proteins, serving as a scaffolding. The majority of endogenous MDM2 is bound to p300/CBP in the nucleus.

How does overexpression of Mdm2 affect DNA repair?

Mdm2 overexpression was shown to inhibit DNA double-strand break repair mediated through a novel, direct interaction between Mdm2 and Nbs1 and independent of p53. Regardless of p53 status, increased levels of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, caused delays in DNA break repair, chromosomal abnormalities, and genome instability.

Is the Mdm2 capable of auto polyubiquitination?

Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals.