The Mdm2 and p53 genes are conserved in the Arachnids

Lane, David P.; Cheok, Chit Fang; Brown, Christopher J.; Madhumalar, Arumugam; Ghadessy, Farid J.; Verma, Chandra

doi:10.4161/cc.9.4.10616

Cited by 26 publications

(31 citation statements)

References 13 publications

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“…With some more detailed information on the location and composition of the different trans-active sequences, it might be possible to compare conserved functions between species and, via this route, predict the original p53 activity that once initiated its function as a tumour suppressor. The TAI contains the BoxI domain, which is the most conserved part of this region of p53, which might indicate that the activity of this domain, such as G1 arrest, is fundamental for the evolution of p53 (Lane et al, 2010). However, as BoxI also forms the binding site for Mdm2 and its close homologue MdmX, and as the binding of Mdm2 to p53 appears early on in evolution, these types of predictions are difficult.…”

Section: P53 Isoforms Unravel P53 Functional Domainsmentioning

confidence: 99%

p53 isoforms gain functions

Olivares‐Illana

Fåhræus

2010

Oncogene

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Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis. One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response. It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions. The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest. On the other hand, p53 itself induces G1 arrest and has no effect on the G2. The two isoforms D133p53, which lacks the first 133 amino acids, and p53b, which carries an alternative C-terminus, are derived from alternative promoter usage or splicing, respectively, and are together implied in controlling cellular senescence. Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses. This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains.

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Section: P53 Isoforms Unravel P53 Functional Domainsmentioning

confidence: 99%

p53 isoforms gain functions

Olivares‐Illana

Fåhræus

2010

Oncogene

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“…We can readily recognize p63/p73 ancestors in choanoflagellates, sea anemones, fruit flies, and roundworms 104 and p53 and MDM2 homologs in placozoans and spiders. 105 In these invertebrates, in every case where the functions of these gene products have been explored, the p53, p63, and p73 genes play a role in protecting the germline cells from DNA damage or starvation (glucose deprivation). Under these stress conditions, p53 family genes respond with cell death of germline cells, preventing developmental defects and monitoring the fidelity of the offspring.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

The Regulation of Multiple p53 Stress Responses is Mediated through MDM2

2012

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The MDM2 oncogene is a key negative regulator of the p53 tumor suppressor protein. MDM2 and p53 form an autoregulatory feedback loop to tightly control the proper cellular responses to various stress signals in order to prevent mutations and tumor formation. The levels and function of the MDM2 protein, an E3 ubiquitin ligase, are regulated by a wide variety of extracellular and intracellular stress signals through distinct signaling pathways and mechanisms. These signals regulate the E3 ubiquitin ligase activity of MDM2, the ability of MDM2 to interact with p53 and a number of other proteins, and the cellular localization of MDM2, which in turn impact significantly upon p53 function. This review provides an overview of the regulation of MDM2 activities by the signals and factors that regulate the MDM2 protein, including genotoxic stress signals, oncogenic activation, cell cycle transition, ribosomal stress, chronic stress, neurohormones, and microRNAs. Disruption of the proper regulation of the MDM2-p53 negative feedback loop impacts significantly upon the frequency of tumorigenesis in a host. A better understanding of the complex regulation of MDM2 and its impact upon p53 function in cells under different conditions will help to develop novel and more effective strategies for cancer therapy and prevention.

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“…A p53-induced protein that feeds back on the p53 pathway to modulate the p53 response in zebrafish [7][8][9] In human cell lines the small molecule CDK inhibitor, roscovitine, has been shown to increase wild-type p53 protein levels and induce p53 dependent transcription probably by both nucleolar disruption and the reduction of Mdm2 levels. 10 In 2002, a short isoform of ZFp53 RNA was found in roscovitine Isoforms of p53 have been described in both zebrafish and human systems based on sensitive analysis of RNA using pCR-based methods.…”

Section: Detection Of the 113p53 Protein Isoformmentioning

confidence: 99%

“…

Lane (2010) Detection of the 113p53 protein isoform: A p53-induced protein that feeds back on the p53 pathway to modulate the p53 response in zebrafish, Cell

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mentioning

confidence: 99%