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The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy
Review

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

Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
Contributed equally.
Academic Editors: Maja T. Tomicic and Thomas Efferth
Cancers 2021, 13(12), 2885; https://doi.org/10.3390/cancers13122885
Received: 13 May 2021 / Revised: 2 June 2021 / Accepted: 3 June 2021 / Published: 9 June 2021
(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)
The p53 family of proteins comprises p53, p63, and p73, which share high structural and functional similarity. The two distinct promoters of each locus, the alternative splicing, and the alternative translation initiation sites enable the generation of numerous isoforms with different protein-interacting domains and distinct activities. The co-expressed p53/p73 isoforms have significant but distinct roles in carcinogenesis. Their activity is frequently impaired in human tumors including colorectal carcinoma due to dysregulated expression and a dominant-negative effect accomplished by some isoforms and p53 mutants. The interactions between isoforms are particularly important to understand the onset of tumor formation, progression, and therapeutic response. The understanding of the p53/p73 network can contribute to the development of new targeted therapies.
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. View Full-Text
Keywords: p53 isoforms; p73 isoforms; colorectal cancer; p53 family; isoform crosstalk p53 isoforms; p73 isoforms; colorectal cancer; p53 family; isoform crosstalk
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MDPI and ACS Style

Horvat, A.; Tadijan, A.; Vlašić, I.; Slade, N. p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies. Cancers 2021, 13, 2885. https://doi.org/10.3390/cancers13122885

AMA Style

Horvat A, Tadijan A, Vlašić I, Slade N. p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies. Cancers. 2021; 13(12):2885. https://doi.org/10.3390/cancers13122885

Chicago/Turabian Style

Horvat, Anđela, Ana Tadijan, Ignacija Vlašić, and Neda Slade. 2021. "p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies" Cancers 13, no. 12: 2885. https://doi.org/10.3390/cancers13122885

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