p53 isoform profiling in glioblastoma and injured brain

Takahashi, Rie; Giannini, Caterina; Sarkaria, Jann N.; Schroeder, Mark A.; Rogers, Joseph; Mastroeni, Diego; Scrable, Heidi

doi:10.1038/onc.2012.322

Cited by 43 publications

(60 citation statements)

References 55 publications

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“…Based on the observation that different p53 isoforms can be differentially expressed in tumors compared with normal tissue, an importance of alternative isoforms in carcinogenesis became clear [174,175,176]. For example, abnormal expression of p53 isoforms was reported in acute myeloid leukemia (AML), cholangiocarcinoma, colon carcinoma, glioblastoma, head and neck tumors, lung tumors, and ovarian tumors [177,178,179,180,181,182]. It was shown that normal breast tissue expresss p53α, p53β, and p53γ, whereas the expression of p53β and p53γ is lost in 60% of breast tumors, which instead frequently overexpress the isoform Δ133p53 [183].…”

Section: Inducible/modified Proteoforms Of P53mentioning

confidence: 99%

p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

Uversky

2016

IJMS

165

123

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Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered regions crucial for its functionality, can form both homo-tetramers and isoform-based hetero-tetramers, and is able to interact with many binding partners. It contains numerous posttranslational modifications, has several isoforms generated by alternative splicing, alternative promoter usage or alternative initiation of translation, and is commonly mutated in different cancers. Therefore, p53 serves as an important illustration of the protein structure–function continuum concept, where the generation of multiple proteoforms by various mechanisms defines the ability of this protein to have a multitude of structurally and functionally different states. Considering p53 in the light of a proteoform-based structure–function continuum represents a non-canonical and conceptually new contemplation of structure, regulation, and functionality of this important protein.

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Section: Inducible/modified Proteoforms Of P53mentioning

confidence: 99%

p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

Uversky

2016

IJMS

165

123

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“…The UPR is not restricted to tumours only, as conditions of insufficient perfusion take place in non-cancerous ischemic tissues and the UPR is also associated with neurological disorders, diabetes and inflammation. The expression of p53/47 in normal and tumour tissues has been difficult to estimate as there is no antibody sufficiently specific for this isoform to carry out immunohistochemistry but more recent studies have shown that some tumour types overexpress p53/47 and it will be interesting to determine how this correlates with levels of ER stress and the response to genotoxic treatments 27 .…”

Section: -3-3 Promotermentioning

confidence: 99%

“…Genomic profiling has implicated p53/47 in differentiating p53 transactivation and more recent data have, in addition to cell cycle control, linked p53/47 activity to the mammalian target of rapamycin metabolic pathway and mitochondria 16,23,26 . Recent studies also identified p53/47 expression in glioblastoma and suggested a role for p53/47 in ageing and stem cell pluripotency 27,28 .…”

mentioning

confidence: 99%

“…However, it is yet relatively unknown how the activity of p53 downstream factors is synchronized to ensure that the cellular response matches the inflicting damage. The p53 gene encodes various p53 isoforms, each with its own unique activity that help to diversify p53 function in response to different signalling pathways [11][12][13][14][15] . The p53/47 isoform, later called DNp53 or D40p53, lacks the first 40 amino acids of the full-length p53 (p53 FL) and has different activity and stability [16][17][18][19] .…”

mentioning

confidence: 99%

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Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A

Mlynarczyk

Fåhræus

2014

Nat Commun

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Endoplasmic reticulum (ER) stress occurs in poorly perfused tissues and activates the p53 isoform p53/47 to promote G2 arrest via 14-3-3s. This contrasts with the p21 CDKN1A -dependent G1 arrest caused by p53 following DNA damage. It is not known how cells respond to conditions when both pathways are activated. Here we show that p53/47 prevents p53-induced p21 transcription during ER stress and that both isoforms repress p21 mRNA translation. This prevents p21 from promoting COP1-mediated 14-3-3s degradation and leads to G2 arrest. DNA damage does not result in p53-dependent induction of p21 during ER stress and instead results in an increase in p53-induced apoptosis. This illustrates how p53 isoforms target an intrinsic balance between the G1 and G2 checkpoints for cell cycle coordination and demonstrates an ER stress-dependent p53 pathway that suppresses p21 and lowers the apoptotic threshold to genotoxic drugs.

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“…Glioblastomas multiforme have been proposed to arise from the subventricular zone stem cell niche. Therefore, it is essential to note that D40p53 is expressed in subventricular zone progenitor cells, decreases with age, and reflects loss of multipotency (24). Expression of this embryonic p53 isoform might be a marker for CSCs in glioma and other CSC-enriched tumor entities, such as breast cancer.…”

Section: Dn Variants Act As Crucial Regulators Of Emtmentioning

confidence: 99%

Emerging from the shade of p53 mutants: N-terminally truncated variants of the p53 family in EMT signaling and cancer progression

Engelmann

Pützer

2014

Sci. Signal.

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The prevailing view has been that N-terminally truncated p53 family isoforms (ΔNp53, ΔNp63, and DNp73) predominantly counteract cell cycle arrest and apoptosis. Recent progress in the field extend these well-known functions and place these isoforms in the center of a comprehensive regulatory network controlling major epithelial-to-mesenchymal transition (EMT)-relevant signaling pathways [such as transforming growth factor-β (TGF-β), wingless-int (WNT), insulin-like growth factor (IGF), and signal transducer and activator of transcription (STAT)], microRNAs, and EMT-associated transcription factors that promote invasion, loss of tumor cell polarity, and metastatic behavior in conjunction with a chemoresistant phenotype. These observations add new weight to the concept that currently underappreciated truncated forms of this tumor suppressor family play an equally important role in promoting cancer aggressiveness as do mutant p53 proteins, and illustrate how the consequences of ΔN/DN expression depend on cellular contexts. The tumor microenvironment contributes to the emergence of these variants, thereby linking inflammation to the activation of the mesenchymal program. In addition, molecular connections between ΔN/DN forms and self-renewal have arisen, suggesting their potential function in the generation of cancer stem cells (CSCs) from bulk tumor cells. These intriguing insights provoke a new understanding of the acquisition of aggressive traits by carcinoma cells in the absence of p53 mutations, and may help direct the development of new therapies for a broad range of cancers.

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p53 isoform profiling in glioblastoma and injured brain

Cited by 43 publications

References 55 publications

p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A

Emerging from the shade of p53 mutants: N-terminally truncated variants of the p53 family in EMT signaling and cancer progression

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