CCAAT/enhancer-binding protein alpha is a protein encoded by the CEBPA gene in humans. [5] [6] CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. [7] For details on the CCAAT structural motif in gene enhancers and on CCAAT/Enhancer Binding Proteins see the specific page.
The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain promoters and gene enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma, as well as distinct transcription factors such as c-Jun. The encoded protein is a key regulator of adipogenesis (the process of forming new fat cells) and the accumulation of lipids in those cells, as well as in the metabolism of glucose and lipids in the liver. [8] The protein has been shown to bind to the promoter and modulate the expression of the gene encoding leptin, a protein that plays an important role in body weight homeostasis. Also, the encoded protein can interact with CDK2 and CDK4, thereby inhibiting these kinases and causing cultured cells to stop dividing. [9] In addition, CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal acute myeloid leukemia. [10]
There are two major categories which CEBPA mutations can be categorized into. One category of mutations prevent CCAAT/enhancer-binding protein alpha DNA binding by altering its COOH-terminal basic leucine zipper domain. The other category of mutations disrupt the translation of the CCAAT/enhancer-binding protein alpha NH2 terminus. CEBPA mutations, which result in diminished CCAAT/enhancer-binding protein alpha activity, contribute to the transformation of myeloid antecedents. [11]
CEBPA has been shown to interact with Cyclin-dependent kinase 2 [12] and Cyclin-dependent kinase 4. [12]
It has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric acute myeloid leukemia patients. [13]
Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors. This includes excessive proliferation of blasts, and blocking the hematopoiesis of granulocytes. It has been shown that suppression of CEBPA expression and blocking of CCAAT/enhancer-binding protein alpha stops the differentiation of myeloid progenitors. For this reason, CCAAT/enhancer-binding protein alpha's role during granulocyte differentiation and CEBPA's role as a tumor suppressor gene is critically important in the prognosis of acute myeloid leukemia. [14]
CCAAT/enhancer-binding protein alpha, the transcription factor that is encoded by CEBPA, is very important in the differentiation of immature granulocytes. Mutation of the CEBPA gene has been shown to play a crucial role in leukemogenesis and prognosis in acute myeloid leukemia patients. In recent studies CEBPA mutations were found in between 7% and 15% of patients with acute myeloid leukemia. The three different types of mutations seen in these AML patients include germ-line N-terminal mutation, N-terminal frameshift mutation, and C-terminal mutation. These mutations are most frequently found in acute myeloid leukemia M1 or acute myeloid leukemia M2. Many reports link CEBPA mutations with a favorable outcome in acute myeloid leukemia. This is because these mutations are likely to induce differentiation arrest in these patients. Patients with CEBPA mutations have longer remission duration and survival time than those without the mutations. [11] Therefore, the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease. [15]
Recently it has been shown that epigenetic modification of the distal promoter region of CEBPA has resulted in downregulation of CEBPA expression in pancreatic cancer cells, lung cancer, and head and neck squamous cell carcinoma. [16] [17]
A recent study has found that higher levels of CEBPA methylation are directly proportionate with treatment response. The complete response rate increased proportionately with the level of CEBPA methylation. For this reason it has been proposed that methylation of CEBPA could be a very useful biomarker in acute myeloid leukemia prognosis. [18]
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation.
Acute promyelocytic leukemia is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week. Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.
CCAAT-enhancer-binding proteins is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators that in turn can open up chromatin structure or recruit basal transcription factors.
Granulopoiesis is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. Granulopoiesis takes place in the bone marrow. It leads to the production of three types of mature granulocytes: neutrophils, eosinophils and basophils.
The granulocyte colony-stimulating factor receptor (G-CSF-R) also known as CD114 is a protein that in humans is encoded by the CSF3R gene. G-CSF-R is a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF). The G-CSF receptors belongs to a family of cytokine receptors known as the hematopoietin receptor family. The granulocyte colony-stimulating factor receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages.
Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.
CCAAT/enhancer-binding protein delta is a protein that in humans is encoded by the CEBPD gene.
Core-binding factor subunit beta is a protein that in humans is encoded by the CBFB gene.
Histone-lysine N-methyltransferase 2A also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX) is an enzyme that in humans is encoded by the KMT2A gene.
Cux1 is a homeodomain protein that in humans is encoded by the CUX1 gene.
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.
CCAAT/enhancer binding protein (C/EBP), epsilon, also known as CEBPE and CRP1, is a type of ccaat-enhancer-binding protein. CEBPE is its human gene and is pro-apoptotic.
T-cell leukemia homeobox protein 3 is a protein that in humans is encoded by the TLX3 gene.
CCAAT/enhancer-binding protein gamma is a protein that in humans is encoded by the CEBPG gene.
Homeobox protein Hox-A6 is a protein that in humans is encoded by the HOXA6 gene.
In molecular biology MicroRNA-223 (miR-223) is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-223 is a hematopoietic specific microRNA with crucial functions in myeloid lineage development. It plays an essential role in promoting granulocytic differentiation while also being associated with the suppression of erythrocytic differentiation. miR-223 is commonly repressed in hepatocellular carcinoma and leukemia. Higher expression levels of miRNA-223 are associated with extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach and recurrent ovarian cancer. In some cancers the microRNA-223 down-regulation is correlated with higher tumor burden, disease aggressiveness, and poor prognostic factors. MicroRNA-223 is also associated with rheumatoid arthritis, sepsis, type 2 diabetes, and hepatic ischemia.
Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
