The Δ133p53 Isoforms, Tuners of the p53 Pathway

Abstract

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.

ΔNp73, TAp73 and Δ133p53 Extracellular Vesicle Cargo as Early Diagnosis Markers in Colorectal Cancer

“…Δ133p53 may act as a survival factor [ 23 ], inhibits senescence [ 30 ], interferes with p53-mediated apoptosis [ 25 , 29 ], induces chemoresistance [ 24 ], and promotes invasion capacity through the epithelial–mesenchymal transition [ 33 ]. Similar to ΔNp73, Δ133p53 may function as an oncogene by acting as a dominant-negative inhibitor of other p53 family members and transactivating a specific set of pro-tumoral effectors [ 26 , 28 ], such as DNA-repair genes [ 29 , 30 ], the JAK-STAT3 and RhoA-ROCK signaling pathways [ 31 ], pro- and antiangiogenic factors [ 32 ] and EMT and stem genes. Δ133p53 has been observed to be upregulated in several tumor types, such as colorectal, lung, breast, prostate and esophageal squamous cell carcinomas and melanoma, and associated with poorer survival rates [ 28 ].…”

“…Similar to ΔNp73, Δ133p53 may function as an oncogene by acting as a dominant-negative inhibitor of other p53 family members and transactivating a specific set of pro-tumoral effectors [ 26 , 28 ], such as DNA-repair genes [ 29 , 30 ], the JAK-STAT3 and RhoA-ROCK signaling pathways [ 31 ], pro- and antiangiogenic factors [ 32 ] and EMT and stem genes. Δ133p53 has been observed to be upregulated in several tumor types, such as colorectal, lung, breast, prostate and esophageal squamous cell carcinomas and melanoma, and associated with poorer survival rates [ 28 ]. Additionally, Arsic N et al associated Δ133p53 upregulation with a higher risk of metastatic recurrence in CRC patients [ 25 ].…”

“…Thus, similar to ΔNp73, the N-terminal truncated TP53 variant Δ133p53 may function as an oncogene by acting as a dominant-negative inhibitor of other p53 family members and transactivating a specific set of pro-tumoral effectors [ 26 , 27 , 28 ]. Accordingly, Δ133p53 may transactivate DNA-repair genes [ 29 , 30 ] and favor resistance processes, regulate the JAK-STAT3 and RhoA-ROCK signaling pathways promoting cell growth and invasion [ 31 ] and modulate pro- and antiangiogenic factors [ 32 ].…”

“…In addition, Δ133p53 associates with an enhanced cancer stem cell phenotype and may induce the epithelial to mesenchymal transition (EMT) in cancer cells [ 33 ] and favor an immunosuppressive environment [ 34 ]. Δ133p53 has been observed to be upregulated in several tumor types, such as colorectal, lung, breast, prostate and esophageal squamous cell carcinomas and melanoma, and has been associated with poorer survival rates [ 28 ].…”

Toward Cancer Diagnostics of the Tumor Suppressor p53 by Surface Enhanced Raman Spectroscopy

“…Under cellular stress conditions, such as DNA damage and oncogenic stresses, p53 is activated giving rise to multiple biological processes that lead to repair genome mutations or to cell-cycle arrest, apoptosis and senescence, if the damage is irreparable [ 3 ]. p53 was found to be inactivated in several tumors, through either mutations in the TP53 gene or a deregulation of its associated path [ 6 , 7 , 8 , 9 ]. On the other hand, p53 is overexpressed in many tumors, as due, e.g., to specific oncogenic stresses or MDM2 gene alterations.…”