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 CCAAT/enhancer binding protein alpha (C/EBPalpha or CEBPA) is the founding member of a family of related leucine zipper transcription factors that play important roles in myeloid differentiation. Targeted inactivation of C/EBPalpha in mice demonstrates its importance in the proper development and function of liver, adipose tissue, lung and haematopoietic tissues. C/EBPalpha is highly expressed in these differentiated tissues where it controls differentiation-dependent gene expression and inhibits cell proliferation. Learning more about the precise molecular functions of the C/EBPalpha protein and how these are affected by leukaemogenic mutations should lead to an improved understanding of the cellular functions that are disrupted in patients with AML. Decreased expression of C/EBPalpha but not C/EBPalpha mutation has been shown in patients with granulocytic leukaemias that are associated with translocations t(8;21), inv (16) or t(15;17). Derived fusion proteins repress C/EBPalpha expression. Differentiation therapy of some AML types is based on restoring C/EBPalpha function. However, apparently normal C/EBPalpha is overexpressed in BCP-ALL harbouring the translocation t(14; 19)(q32; q13). C/EBPalpha may exhibit oncogenic as well as tumour suppressor properties in human leukaemogenesis. C/EBPalpha mutations were not found in non-haematopoietic cancers. DNA hypermethylation of the upstream C/EBPalpha promoter region is responsible for very low C/EBPalpha expression in human lung and endometrial cancer. C/EBPalpha expression may be a biomarker for early detection of these cancers and DNA-modifying drugs such as demethylating agents and/or histone deacetylase inhibitors could be used in the treatment of these malignancies.
 ...
PMID:Growth-inhibiting activity of transcription factor C/EBPalpha, its role in haematopoiesis and its tumour suppressor or oncogenic properties in leukaemias. 1758

A loss-of-function mutation of TET2, CBL and CEBPA has been implicated in the pathogenesis or leukaemic transformation of myeloproliferative neoplasm. As tumour suppressor genes may potentially be inactivated by promoter hypermethylation, the authors studied the methylation status of these genes in three cell lines and diagnostic marrow samples from 45 patients with myeloproliferative neoplasm (MPN) (essential thrombocythaemia, N=34; polycythaemia vera, N=7 and primary myelofibrosis, N=4) by methylation-specific PCR. TET2 was heterozygously methylated in MEG-01 and K562 but completely unmethylated in HEL. On the other hand, both CBL and CEBPA were completely unmethylated in all three cell lines. In the primary marrow samples, methylation of TET2 occurred in two (5.9%) patients with essential thrombocythaemia (4.4% of all patients), both without JAK2 V617 mutation, but not in polycythaemia vera or primary myelofibrosis. There was no association between TET2 methylation with the type of MPN (p=0.713). Hypermethylation of CBL or CEBPA was not detected in any patients. In summary, methylation of TET2, CBL and CEBPA is infrequent in MPN at diagnosis. The role of methylation of these genes at the time of leukaemic transformation warrants further study.
 ...
PMID:Methylation of TET2, CBL and CEBPA in Ph-negative myeloproliferative neoplasms. 2067 Oct 51

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.
 ...
PMID:Mediator kinase inhibition further activates super-enhancer-associated genes in AML. 2641 49