Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of pituitary tumor-transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TRbeta(PV/PV) mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG1 was physically associated with thyroid hormone beta receptor (TRbeta) as well as its mutant, designated PV. Concomitant with thyroid hormone-induced (T3-induced) degradation of TRbeta, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRbeta was activated by the direct interaction of the liganded TRbeta with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28gamma. PV, which does not bind T3, could not interact directly with SRC-3/PA28gamma to activate proteasome degradation, resulting in elevated PTTG1 levels. The accumulated PTTG1 impeded mitotic progression in cells expressing PV. Our results unveil what we believe to be a novel mechanism by which PTTG1, an oncogene, is regulated by the liganded TRbeta. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis.
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PMID:Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. 1703 56

Selective protein degradation via the ubiquitin-26S proteasome is a major mechanism underlying DNA replication and cell division in all eukaryotes. In particular, the APC/C (anaphase promoting complex or cyclosome) is a master ubiquitin protein ligase (E3) that targets PDS1/SECURIN and cyclin B for degradation allowing sister chromatid separation and exit from mitosis, respectively. Interestingly, it has been found that the APC/C remains active in differentiated neurons in which the E3 ligase regulates axon growth, neuronal survival and synaptic functions. However, despite these recent findings, the role of APC/C in differentiated cells and the regulation of its activity beyond cell division is still poorly understood. Here, we investigate the activity and function of APC/C in the model plant Arabidopsis thaliana. We used cyclin reporter constructs to follow APC/C activity during plant development and found that this E3 ligase remains active in most post-mitotic plant cells. Strikingly, hypomorphic mutant lines, in which the APC/C activity is reduced, exhibited several developmental abnormalities, including defects in cotyledon vein patterning and internode elongation leading to a characteristic broomhead-like phenotype. Histological analyses revealed an increased amount of vascular tissue, most notably xylem and lignified sclerenchyma, indicating a role for APC/C in plant vasculature development and organization.
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PMID:The APC/C E3 ligase remains active in most post-mitotic Arabidopsis cells and is required for proper vasculature development and organization. 1933 65

The largest E3 ubiquitin-ligase complex, known as anaphase-promoting complex/cyclosome (APC/C), regulates the proteolysis of cell cycle regulators such as CYCLIN B and SECURIN that are essential for sister-chromatid separation and exit from mitosis. Despite its importance, the role of APC/C in plant cells and the regulation of its activity during cell division remain poorly understood. Here, the Arabidopsis thaliana APC/C subunit APC10 was characterized and shown to functionally complement an apc10 yeast mutant. The APC10 protein was located in specific nuclear bodies, most probably resulting from its association with the proteasome complex. An apc10 Arabidopsis knockout mutant strongly impaired female gametogenesis. Surprisingly, constitutive overexpression of APC10 enhanced leaf size. Through kinematic analysis, the increased leaf size was found to be due to enhanced rates of cell division during the early stages of leaf development and, at the molecular level, by increased APC/C activity as measured by an amplification of the proteolysis rate of the mitotic cyclin, CYCB1;1.
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PMID:The APC/C subunit 10 plays an essential role in cell proliferation during leaf development. 2171