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D'Orazio, J. A.

Publications and source records attributed to D'Orazio, J. A..

2 recordsLinked to original sources

A new species of planarian flatworm from Mexico: Girardia guanajuatiensis

Planarian flatworms are best known for their impressive regenerative capacity, yet this trait varies across species. In addition, planarians have other features that share morphology and function with the tissues of many other animals, including an outer mucociliary epithelium that drives planarian locomotion and is very similar to the epithelial linings of the human lung and oviduct. Planarians occupy a broad range of ecological habitats and are known to be sensitive to changes in their environment. Yet, despite their potential to provide valuable insight to many different fields, very few planarian species have been developed as laboratory models for mechanism-based research. Here we describe a previously undocumented planarian isolate, Girardia sp. (Guanajuato). After collecting this isolate from a freshwater habitat in central Mexico, we characterized it at the morphological, cellular, and molecular level. We show that Girardia sp. (Guanajuato) shares features with animals in the Girardia genus but also possesses traits that appear unique to this isolate. By thoroughly characterizing this new planarian isolate, our work facilitates future comparisons to other flatworms and further molecular dissection of the unique and physiologically-relevant traits observed in this Girardia sp. (Guanajuato) isolate.

developmental biology↗

Integrin α6β4 signaling switches DNA repair from homologous recombination to non-homologous end-joining pathway to sensitize breast cancer cells to cisplatin

Integrin 6{beta}4 is highly expressed in triple negative breast cancer (TNBC) and drives aggressiveness by stimulating proliferation, angiogenesis, cell migration, invasion and metastasis. Signaling from this integrin stimulates DNA repair and apoptosis resistance, suggesting that it could contribute to therapeutic resistance. Upon testing this hypothesis, we found that integrin 6{beta}4 signaling promoted a three-fold greater sensitivity to cisplatin but exhibited no difference in response to other chemotherapies tested. Mechanistic investigations revealed that integrin 6{beta}4 stimulated quicker and higher amplitude of activation of ATM, Chk2, p53, and 53BP1, which required the integrin {beta}4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin 6{beta}4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we discovered that integrin 6{beta}4 preferentially activated DNA-PKc in response to cisplatin, which led to formation of DNA-PKc-p53 complexes and 53BP1 activation. As a result, integrin 6{beta}4 shifted double strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ). In summary, we discovered a novel function of integrin 6{beta}4 in switching DSB repair from HR to NHEJ that results in cisplatin sensitivity in TNBC.

cancer biology↗