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Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.
This article was published in the following journal.
Name: Nature cell biology
The anaphase-promoting complex/cyclosome (APC/C) is a large, multi-subunit ubiquitin ligase involved in regulation of cell division. APC/C substrate specificity arises from binding of short degron mot...
The expression of multiple growth-promoting genes is coordinated by the transcriptional co-activator Yorkie with its major regulatory input provided by the Hippo-Warts kinase cascade. Here, we identif...
piRNA clusters are thought to repress transposable element activity in mammals and invertebrates. Here, we used a simple population genetics model to reveal the constraint on the size of piRNA cluster...
The piRNA pathway protects germline genomes from selfish genetic elements (e.g. transposons) through their transcript cleavage in the cytoplasm and/or their transcriptional silencing in the nucleus. H...
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A subunit of the anaphase-promoting complex whose primary function is to provide structural support for the catalytic and substrate-recognition modules of the complex. Apc4, along with Apc5, tethers the tetratricopeptide-coactivator binding subcomplex to the main structural subunit, Apc1.
A subunit of the anaphase-promoting complex whose primary function is to provide structural support for the catalytic and substrate-recognition modules of the complex. Apc5, along with Apc4, tethers the tetratricopeptide-coactivator binding subcomplex to the main structural subunit, Apc1.
An E3 ubiquitin ligase primarily involved in regulation of the metaphase-to-anaphase transition during MITOSIS through ubiquitination of specific CELL CYCLE PROTEINS. Enzyme activity is tightly regulated through subunits and cofactors, which modulate activation, inhibition, and substrate specificity. The anaphase-promoting complex, or APC-C, is also involved in tissue differentiation in the PLACENTA, CRYSTALLINE LENS, and SKELETAL MUSCLE, and in regulation of postmitotic NEURONAL PLASTICITY and excitability.
Apc10 is necessary for coactivator-dependent substrate recognition by the anaphase-promoting complex-cyclosome. It binds the Apc2 subunit, which is a part of the catalytic core, and interacts with coactivators Cdh1 or Cdc20 to recruit substrates to the complex.
The largest subunit of the anaphase-promoting complex. It acts primarily as a scaffold for the proper organization and arrangement of subunits. The C-terminal region of Apc1 contains a series of tandem amino acid repeats that are also seen in the 26S proteasome regulatory particle, and may assist with forming and stabilizing protein-protein interactions.
The pancreas secretes a number of important hormones into the digestive tract and the blood stream. Cancers are most commonly exocrine than endocrine (neuroendocrine) tumors. Functional tumors secrete hormones; Insulinoma, Gastrinoma, Somatostatinoma, VI...
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Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...