Tissue-specific roles of p73 in development and homeostasis

Nemajerová, Alice; Moll, Ute M.

doi:10.1242/jcs.233338

Cited by 34 publications

(36 citation statements)

References 74 publications

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“…In addition to the numerous functions of p73 more or less closely related to tumorigenesis, during the last decade, many non-oncogenic functions of p73 emerged mainly due to extensive research on the isoform-specific knockout models [219,256]. p73 plays an essential role in neuronal development, with the TAp73 isoform playing a more crucial role in neural development and homeostasis compared to ∆Np73 [256]. TAp73 contributes to the long-term maintenance of neural stem cells via transcriptional regulation of the bHLH Hey2, which prevents their differentiation [257].…”

Section: Biological Activity and Functions Of The P73 Isoformsmentioning

confidence: 99%

p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies

Horvat

Tadijan

Vlašić

et al. 2021

Cancers

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The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease.

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Section: Biological Activity and Functions Of The P73 Isoformsmentioning

confidence: 99%

p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies

Horvat

Tadijan

Vlašić

et al. 2021

Cancers

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“…The Trp73 gene, codifying the p73 proteins, has a complex structure, including two alternative promoters that regulate expression of the N-terminal full-term isoform, TAp73, and the N-terminal truncated ΔNp73 isoform. The crucial role of p73 in the CNS has been highlighted by the phenotype of the several knockout mice for p73: global p73KO mice and the isoform-specific TAp73 or ΔNp73 models [ 101 , 143 ] [ 144 , 145 , 146 , 147 ]. Indeed, deletion of both isoforms results in hippocampal dysgenesis that is characterized by the partial or total loss of the lower blade of the DG and by an impaired organization of CA1 and CA3 regions [ 140 ].…”

Section: Transcriptional Regulation Of Adult Neurogenesismentioning

confidence: 99%

Regulation of Adult Neurogenesis in Mammalian Brain

Niklison-Chirou

Agostini

Amelio

et al. 2020

IJMS

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Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors.

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“…At the organismal level, p73 has been shown to be important for neuronal development, ciliogenesis, and reproduction, amongst others [37]. TAp73 regulates these functions through the activation of a myriad of target genes, and interestingly, many of these developmental targets have not been demonstrated to be regulated by p53 or to contain a typical p53RE [36,124,125].…”

Section: Non-canonical Targets Of Tap73 In Cancersmentioning

confidence: 99%

p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?

Wang

Teo

Sabapathy

2020

IJMS

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Identification of p73 as a structural homolog of p53 fueled early studies aimed at determining if it was capable of performing p53-like functions. This led to a conundrum as p73 was discovered to be hardly mutated in cancers, and yet, TAp73, the full-length form, was found capable of performing p53-like functions, including transactivation of many p53 target genes in cancer cell lines. Generation of mice lacking p73/TAp73 revealed a plethora of developmental defects, with very limited spontaneous tumors arising only at a later stage. Concurrently, novel TAp73 target genes involved in cellular growth promotion that are not regulated by p53 were identified, mooting the possibility that TAp73 may have diametrically opposite functions to p53 in tumorigenesis. We have therefore comprehensively evaluated the TAp73 target genes identified and validated in human cancer cell lines, to examine their contextual relevance. Data from focused studies aimed at appraising if p53 targets are also regulated by TAp73—often by TAp73 overexpression in cell lines with non-functional p53—were affirmative. However, genome-wide and phenotype-based studies led to the identification of TAp73-regulated genes involved in cellular survival and thus, tumor promotion. Our analyses therefore suggest that TAp73 may not necessarily be p53’s natural substitute in enforcing tumor suppression. It has likely evolved to perform unique functions in regulating developmental processes and promoting cellular growth through entirely different sets of target genes that are not common to, and cannot be substituted by p53. The p53-related targets initially reported to be regulated by TAp73 may therefore represent an experimental possibility rather than the reality.

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Tissue-specific roles of p73 in development and homeostasis

Cited by 34 publications

References 74 publications

p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies

p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies

Regulation of Adult Neurogenesis in Mammalian Brain

p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?

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