Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor is regulated mainly by Mdm2, an E3 ubiquitin ligase that promotes the ubiquitylation and proteasome-mediated degradation of p53. Many agents that induce p53 are inhibitors of transcription, suggesting that the p53 pathway can detect a signal(s) arising from transcriptional malfunction. Mdm2 associates with TAFII250, a component of the general transcription factor TFIID. Inactivation of TAFII250 in ts13 cells, which express a temperature-sensitive mutant of TAFII250, leads to the induction of p53 and cell cycle arrest. In the present study, we show that TAFII250 stimulates the ubiquitylation and degradation of p53 in a manner that is dependent upon Mdm2 and requires its acidic domain. Mechanistically, TAFII250 downregulates Mdm2 auto-ubiquitylation, leading to Mdm2 stabilization, and promotes p53-Mdm2 association through a recently defined second binding site in the acidic domain of Mdm2. These data provide a novel route through which TAFII250 can directly influence p53 levels and are consistent with the idea that the maintenance of p53 turnover is coupled to the integrity of RNA polymerase II transcription.
 ...
PMID:Transcription factor TAFII250 promotes Mdm2-dependent turnover of p53. 1723 21

The TAF4 subunit of transcription factor TFIID was inactivated in the basal keratinocytes of foetal and adult mouse epidermis. Loss of TAF4 in the foetal epidermis results in reduced expression of the genes required for skin barrier function, leading to early neonatal death. By contrast, TAF4 inactivation in adult epidermis leads to extensive fur loss and an aberrant hair cycle characterised by a defective anagen phase. Although the mutant epidermis contains few normal anagen-phase hair follicles, many genes expressed at this stage are strongly upregulated indicating desynchronized and inappropriate gene expression. The TAF4 mutant adult epidermis also displays interfollicular hyperplasia associated with a potent upregulation of several members of the EGF family of mitogens. Moreover, loss of TAF4 leads to malignant transformation of chemically induced papillomas and the appearance of invasive melanocytic tumours. Together, our results show that TAF4 is an important regulator of keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity.
 ...
PMID:The TFIID subunit TAF4 regulates keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity in mouse epidermis. 1762 60

Induction and activation of the p53 tumour suppressor protein occurs in response to a number of cellular stresses, including disruption of RNA polymerase II-mediated transcription. Both p53 itself and its principle negative regulator, the E3 ubiquitin ligase Mdm2, are substrates for phosphorylation by the protein kinase CK2 in vitro. CK2 phosphorylates Mdm2 within its central acidic domain, a region that is critical for making a second point of contact with p53 and mediating p53 ubiquitylation and turnover. Additionally, there is evidence that CK2 interacts with, and regulates, both p53 and Mdm2 within the cell but the molecular mechanisms through which CK2-mediated regulation of the p53 response can occur are only poorly understood. Previously, we showed that the basal transcription factor TAFII250, a critical component of TFIID, can interact with Mdm2 and promote the association of the Mdm2 acidic domain with p53. In the present study, we show that immunoprecipitates of TAFII250, either from mammalian cell extracts or from baculovirus-infected cells expressing elevated levels of HA-tagged TAFII250, can phosphorylate Mdm2 in vitro within its acidic domain. We show that CK2 is tightly associated with TAFII250 and is the principal activity responsible for TAFII250-mediated phosphorylation of Mdm2. Our data fit with recent observations that phosphorylation of the acidic domain of Mdm2 stimulates its association with p53 and are consistent with a model in which recruitment of CK2 by TAFII250 may play a contributory role in the maintenance of Mdm2 phosphorylation and function.
 ...
PMID:Transcription factor TAFII250 phosphorylates the acidic domain of Mdm2 through recruitment of protein kinase CK2. 1854