p53 family in development

The p53 family network is a unique cellular processor that integrates information from various pathways and determines cellular choices between proliferation, replication arrest/repair, differentiation, senescence, or apoptosis. The most studied role of the p53 family is the regulation of stress response and tumor suppression. By removing damaged cells from the proliferating pool, p53 family members preserve the integrity of the genome. In addition to this well recognized role, recent data implicate the p53 protein family in a broader role of controlling cell proliferation, differentiation and death. Members of the p53 protein family with opposing activity perform coordination of these processes. Imbalance of p53 protein family may contribute to a significant proportion of congenital developmental abnormalities in humans.     

The role of CCN family genes in haematological malignancies

Haematological malignancies, although a broad range of specific disease types, continue to show considerable overlap in classification, and patients are treated using similar chemotherapy regimes. In this review we look at the role of the CCN family of matricellular proteins and indicate their role in nine haematological malignancies including both myeloid and lymphoid neoplasms. The potential for further haematological neoplasms with CCN family associations is argued by summarising the demonstrated role of CCN family genes in the differentiation of haematopoietic stem cells (HSC) and mesenchymal stem cells. The expanding field of knowledge encompassing CCN family genes and cancers of the HSC-lineage highlights the importance of extracellular matrix-interactions in both normal physiology and tumorigenesis of the blood, bone marrow and lymph nodes.     

Two molecularly distinct intracellular pathways to oligodendrocyte differentiation: role of a p53 family protein

Both thyroid hormone (TH) and retinoic acid (RA) induce purified rat oligodendrocyte precursor cells in culture to stop division and differentiate. We show that these responses are blocked by the expression of a dominant-negative form of p53. Moreover, both TH and RA cause a transient, immediate early increase in the same 8 out of 13 mRNAs encoding intracellular cell cycle regulators and gene regulatory proteins, but only if protein synthesis is inhibited. Platelet-derived growth factor (PDGF) withdrawal also induces these cells to differentiate, but we show that the intracellular mechanisms involved are different from those involved in the hormone responses: the changes in cell cycle regulators differ, and the differentiation induced by PDGF withdrawal (or that which occurs spontaneously in the presence of PDGF) is not blocked by the dominant-negative p53. These results suggest that TH and RA activate the same intracellular pathway leading to oligodendrocyte differentiation, and that this pathway depends on a p53 family protein. Differentiation that occurs independently of TH and RA apparently involves a different pathway. It is likely that both pathways operate in vivo.     

The role of p53 in nutrients levels

Comment on: Ashur-Fabian O, et al. Cell Cycle 2010; 9:446-7.     

Recognition of cisplatin-damaged DNA by p53 protein: critical role of the p53 C-terminal domain

It was shown previously that the p53 protein can recognize DNA modified with antitumor agent cisplatin (cisPt-DNA). Here, we studied p53 binding to the cisPt-DNA using p53 deletion mutants and via modulation of the p53-DNA binding by changes of the protein redox state. Isolated p53 C-terminal domain (CTD) bound to the cisPt-DNA with a significantly higher affinity than to the unmodified DNA. On the other hand, p53 constructs involving the core domain but lacking the C-terminal DNA binding site (CTDBS) exhibited only small binding preference for the cisPt-DNA. Oxidation of cysteine residues within the CD of posttranslationally unmodified full length p53 did not affect its ability to recognize cisPt-DNA. Blocking of the p53 CTDBS by a monoclonal antibody Bp53-10.1 resulted in abolishment of the isolated CTD binding to the cisPt-DNA. Our results demonstrate a crucial role of the basic region of the p53 CTD (aa 363-382) in the cisPt-DNA recognition.     

The evolution of the p53 family of genes

Comment on: Lane DP, et al. Cell Cycle 2011; 10:4272–9     

The emerging role of p53 in stem cells

Among the hundreds of oncogenes and tumor suppressors that have been identified in the past 50 years, p53 is probably the best characterized; nevertheless, new functions are constantly being discovered. As a tumor suppressor, p53 regulates cellular responses to different stress stimuli by inducing reversible cell cycle arrest and DNA repair, or triggering senescence or apoptosis. Recent findings on the regulation of stem cell (SC) division and reprogramming suggest the intriguing possibility that p53 also carries out its tumor suppression function by regulating SC homeostasis. Specifically, p53 activation may counteract SC expansion by several emerging mechanisms including restriction of self-renewing divisions, inhibition of symmetric division and block of reprogramming of somatic/progenitor cells into SCs.     

The p53 family in nervous system development and disease

The p53 family, consisting of the tumor suppressors p53, p63 and p73, play a vital role as regulators of survival and apoptosis in the developing, adult and injured nervous system. These proteins function as key survival and apoptosis checkpoints in neurons, acting as either rheostats or sensors responsible for integrating multiple pro-apoptotic and survival cues. A dramatic example of this checkpoint function is observed in developing sympathetic neurons, where a pro-survival and truncated form of p73 antagonizes the apoptotic functions of p53 and p63. Thus the levels and activities of the different p53 family members may ultimately determine whether neurons either live or die during nervous system development and disease.     

Dancing with p53: The role of p38MAPK in mitosis of p53-deficient tetraploid cells

Comment on: Vitale I, et al. Cell Cycle 2010; 9:2823-9.     

Interplay between the p53 tumor suppressor protein family and Cdk5

Cyclin-dependent kinases (Cdks) play a key role in orchestrating the coordination of cell cycle progression in proliferating cells. The escape from the proper, control of the cell cycle by the upregulation of cyclins or aberrant activation of Cdks leads to malignant transformation. In quiescent cells and/or terminally differentiated cells, the expression pattern and activity of Cdks is altered. In postmitotic neurons, expression of mitotic kinases is downregulated, whereas Cdk5 expression becomes upregulated. Similarly to other Cdks, free Cdk5 displays no enzymatic activity and requires complex formation with a specific regulatory subunit. Two activators of Cdk5 have been identified. p35 and its isoform p39 bind to, and thereby activate, Cdk5. Unlike mitotic kinases, Cdk5 does not require activating phosphorylation within the T-loop. Because p35 is a short-lived protein, the p35/Cdk5 complexes are unstable. The stability of the p35 protein is regulated by its Cdk5-mediated phosphorylation of p35. Activated p35/Cdk5 kinase phosphorylates numerous physiological targets. The proper phosphorylation of the most important substrates, such as τ protein and neurofilament H, is essential for the correct regulation of the cytoskeletal organization, thereby regulating cell adhesion, motility, and synaptic plasticity. Moreover, Cdk5 regulates the activity of the p53 tumor suppressor via phosphorylation. p53 is upregulated in multiple neuronal death paradigms, including hypoxia, ischemia, and excitotoxicity, and plays a key role in the induction of apoptosis. On the other hand, an abnormally high expression and elevated activity of Cdk5 was observed in neurodegenerative diseases, suggesting the application of Cdk inhibitors for their therapy. Considering the action of some Cdk inhibitors on the expression and activity of the p53 protein, their therapeutic efficacy must be carefully evaluated.     

Neuronal life and death: an essential role for the p53 family

Recent evidence indicates that the p53 tumor suppressor protein, and its related family member, p73, play an essential role in regulating neuronal apoptosis in both the developing and injured, mature nervous system. In the developing nervous system, they do so by regulating naturally-occurring cell death in neural progenitor cells and in postmitotic neurons, acting to ensure the apoptosis of cells that either do not appropriately undergo the progenitor to postmitotic neuron transition, or that fail to compete for sufficient quantities of trophic support. Somewhat surprisingly, in developing postmitotic neurons, p53 plays a proapoptotic role, while a naturally-occurring, truncated form of p73, DeltaNp73, antagonizes p53 and plays an anti-apoptotic role. In the mature nervous system, numerous studies indicate that p53 is essential for the neuronal death in response to a variety of insults, including DNA damage, ischemia and excitotoxicity. It is likely that all of these insults culminate in DNA damage, which may well be a common trigger for neuronal apoptosis. In this regard, the signaling pathways that are responsible for triggering p53-dependent neuronal apoptosis are starting to be elucidated, and involve cell cycle deregulation and activation of the JNK pathway. Finally, accumulating evidence indicates that p53 is perturbed in the CNS in a number of neurodegenerative disorders, leading to the hypothesis that longterm oxidative damage and/or excitotoxicity ultimately trigger p53-dependent apoptosis in the chronically degenerating nervous system.