 | This article has no lead section .(August 2021) |
| Transcriptional factor AF4/FMR2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | AF-4 | ||||||||
| Pfam | PF05110 | ||||||||
| InterPro | IPR007797 | ||||||||
| CATH | 2lm0 | ||||||||
| |||||||||
AF4/FMR2 (AFF) is a family of nuclear transcriptional activators that encourage RNA elongation. [1] There are four genes in this family, all of which reside in the nucleus of the cells. The gene family includes AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31. Within the family, the AFF2/FMR2 is silenced in FRAXE intellectual disability; while the other three gene families will form fusion genes as a consequence of chromosome translocations with the myeloid/lymphoid or mixed lineage leukemia gene in acute lymphoblastic leukemias. While different members of the AF4/FMR2 family are known for playing various roles in cells, they all commonly participate in the regulation of splicing and transcription.
After research and examination, a Drosophila orthologue has been identified. Cells homozygous for a defective mutant of the gene are abnormally small, so the researchers named the gene Lilliputian (Lilli; Q9VQI9). It contains an AT-hook domain. It represents a novel pair-rule gene that acts in cytoskeleton regulation, segmentation and morphogenesis in Drosophila. [2] Like Lilli, human AFF1 and AFF4 participate in the super elongation complex. [3] The AFF1 and AFF4 proteins form this complex by linking positive elongation factor b (P-TEFb) and ELL1/2, which are two transcriptional elongation factors. [4] These genes use chromatin remodeling and elongation to regulate transcription. The Lilli gene identifies the FMR2 functions that are possible, but not specific, in humans and mice. [5]
Human genes include AFF1, AFF2, AFF3, and AFF4. Fusion genes involving AFF1 can produce a rogue activator leading to leukemia. Mutations in AFF2 are implicated in breast cancer. AFF2/FMR2 are found within the placenta and brains on the X chromosome. [1] A trinucleotide repeat disorder involving AFF2 causes X-linked intellectual disability. This is due to the repetition of over 200 genes in the 5’ region of the untranslated helix. With overextension and methylation on this replicated gene (FRM1) is what leads to FRAXE ID - a rare human disease. [2] This condition is known as FRAXE ID where the hippocampal region of the brain is affected in long term potentiation and it causes mental retardation. The FMR2 gene has been identified as a part of several pathways within the body (the transforming growth factor-β pathway, the Raf/MEK/MAP kinase pathway, and the P13K/PKB pathway). [2] Studies have been performed on knockout mice to prove the detrimental effect it has on the body such as infliction on organ growth, cell growth, and cytoskeletal structure.
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.
MCEF or Major Cdk9-interacting elongation factor is a transcription factor related to Af4. It is the fourth member of the Af4 family (AFF) of transcription factors, involved in numerous pathologies, including Acute Lymphoblastic Leukemia (ALL), abnormal CNS development, breast cancer and azoospermia.
The positive transcription elongation factor, P-TEFb, is a multiprotein complex that plays an essential role in the regulation of transcription by RNA polymerase II in eukaryotes. Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes. P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF) and negative elongation factor (NELF), as well as the carboxyl terminal domain of the large subunit of Pol II and this causes the transition into productive elongation leading to the synthesis of mRNAs. P-TEFb is regulated in part by a reversible association with the 7SK snRNP. Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.
In molecular biology 7SK is an abundant small nuclear RNA found in metazoans. It plays a role in regulating transcription by controlling the positive transcription elongation factor P-TEFb. 7SK is found in a small nuclear ribonucleoprotein complex (snRNP) with a number of other proteins that regulate the stability and function of the complex.
Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.
TEAD2, together with TEAD1, defines a novel family of transcription factors, the TEAD family, highly conserved through evolution. TEAD proteins were notably found in Drosophila (Scalloped), C. elegans, S. cerevisiae and A. nidulans. TEAD2 has been less studied than TEAD1 but a few studies revealed its role during development.
Cyclin-T1 is a protein that in humans is encoded by the CCNT1 gene.
Transcription elongation factor SPT5 is a protein that in humans is encoded by the SUPT5H gene.
AF4/FMR2 family member 1 is a protein that in humans is encoded by the AFF1 gene. At its same location was a record for a separate PBM1 gene, which has since been withdrawn and considered an alias. It was previously known as AF4.
Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene. TEAD1 was the first member of the TEAD family of transcription factors to be identified.
RNA polymerase II elongation factor ELL is an enzyme that in humans is encoded by the ELL gene.
Transcription elongation factor SPT4 is a protein that in humans is encoded by the SUPT4H1 gene.
Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.
AF4/FMR2 family member 2 is a protein that in humans is encoded by the AFF2 gene. Mutations in AFF2 are implicated in cases of breast cancer.
Homeobox Protein HB24 is a protein that in humans is encoded by the HLX gene.
AF4/FMR2 family member 3 is a protein that in humans is encoded by the AFF3 gene.
Protein ENL is a protein that in humans is encoded by the MLLT1 gene.
X-linked mental retardation refers to medical disorders associated with X-linked recessive inheritance that result in intellectual disability.
In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.
Ali Shilatifard is an American biochemist/molecular biologist, the Robert Francis Furchgott Professor and Chairman of the department of biochemistry and molecular genetics, and the director of the Simpson Query Institute for Epigenetics at the Northwestern University Feinberg School of Medicine. He has served as a senior editor for the journal Science, and currently serves as the Editor for Science's open access journal Science Advances. Research in Shilatifard's lab focuses on the cause of childhood leukemia through chromosomal translocations, the role of ELL in this process, and the discovery of the Super Elongation Complex as being a central complex linking MLL translocations into a diverse number of genes to leukemic pathogenesis.