Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions.

Defect in Ser312 phosphorylation of Tp53 dysregulates lipid metabolism for fatty accumulation and fatty liver susceptibility: Revealed by lipidomics.

The Tp53 gene is a well-known tumour suppressor, mutation of which (e.g. prevention of Ser312 phosphorylation) induces deletion or expression of an inactive p53 protein to increase the susceptibility of tumour occurance.

Cell autonomous role of iASPP deficiency in causing cardiocutaneous disorders.

Desmosome components are frequently mutated in cardiac and cutaneous disorders in animals and humans and enhanced inflammation is a common feature of these diseases. Previous studies showed that inhibitor of Apoptosis Stimulating p53 Protein (iASPP) regulates desmosome integrity at cell-cell junctions and transcription in the nucleus, and its deficiency causes cardiocutaneous disorder in mice, cattle, and humans. As iASPP is a ubiquitously expressed shuttling protein with multiple functions, a key question is whether the observed cardiocutaneous phenotypes are caused by loss of a cell autonomous role of iASPP in cardiomyocytes and keratinocytes specifically or by a loss of iASPP in other cell types such as immune cells.

Caspase cleavage of iASPP potentiates its ability to inhibit p53 and NF-κB.

An intriguing biological question relating to cell signaling is how the inflammatory mediator NF-kB and the tumour suppressor protein p53 can be induced by similar triggers, like DNA damage or infection, yet have seemingly opposing or sometimes cooperative biological functions. For example, the NF-κB subunit RelA/p65 has been shown to inhibit apoptosis, whereas p53 induces apoptosis. One potential explanation may be their co-regulation by common cellular factors: inhibitor of Apoptosis Stimulating p53 Protein (iASPP) is one such common regulator of both RelA/p65 and p53.

Requirement for phosphorylation of P53 at Ser312 in suppression of chemical carcinogenesis.

The p53 tumour suppressor is activated in response to a wide variety of genotoxic stresses, frequently via post-translational modification. Using a knock in mouse model with a Ser312 to Ala mutation, we show here that phosphorylation of p53 on Ser312 helps to prevent tumour induction by the alkylating agent MNU, which predominantly caused T cell lymphomas. This is consistent with our previous observation that p53(312A/A) mice are more susceptible to X-ray induced tumourigenesis.

Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo.

The tumor suppressor p53 is a master sensor of stress, and posttranslational modifications are key in controlling its stability and transcriptional activities. p53 can be phosphorylated on at least 23 Ser/Thr residues, the majority of which are phosphorylated by stress-related kinases. An exception is Ser315 in human p53 (Ser312 in mouse), which is predominantly phosphorylated by cell cycle-related kinases.

A complex barcode underlies the heterogeneous response of p53 to stress.

The tumour suppressor p53 is activated following stress and initiates a heterogeneous response in a cell-, tissue- and stress-dependent manner. This heterogeneity is reflected in the different physiological outcomes that follow p53 activation. One mechanism that may contribute to this variability is the promoter selectivity of p53 target genes.

ASPP2: a gene that controls life and death in vivo.

The fundamental role of apoptosis in tumor prevention and the important role of p53 in this process are now universally recognized. Recently, several families of p53-binding proteins have been shown to influence p53's decision to direct the cells either into the apoptotic pathway or in cell cycle arrest. Among them, the ASPP family specifically regulate p53-dependent apoptosis.

The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization.

ASPP1 and ASPP2 are both proteins that interact with p53 and enhance its ability to induce apoptosis by selectively elevating the expression of proapoptotic p53-responsive genes. iASPP(RAI) is a third member of the family that is the most conserved inhibitor of p53-mediated apoptosis. Here, we have described iASPP, a longer form of iASPP(RAI), which at 828 amino acids is more than twice the size of iASPP(RAI).

To die or not to die: how does p53 decide?

p53 is frequently mutated in cancer and as a result is one of the most intensely studied tumour suppressors. Analysis of the primitive forms of p53 found in Caenorhabditis elegans and Drosophila, alongside studies using transgenic mouse models, indicate that the induction of apoptosis is both the most conserved function of p53 and vital for tumour suppression. p53-mediated apoptosis occurs through a combination of mechanisms which include pathways that are both dependent and independent of alterations in gene expression.

The ASPP family: deciding between life and death after DNA damage.

It is well established that p53 is a primary target for mutation in human cancer. p53 carries out the important task of ensuring that damaged DNA is not passed on during cell division, a duty that it performs by either inhibiting the cell cycle or inducing apoptosis. However, it is unclear how this decision is made.