Disease relevance of Gfi1

• Heightened expression of Gfi1 distinguishes MZL from other lymphoma types [1].
• Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1 [2].
• Gfi1-deficient mice responded to a pulmonary P. aeruginosa infection with uncontrolled pulmonary release of interleukin (IL)-1 and tumour necrosis factor (TNF)-alpha, sepsis and death, which were delayed by injection of IL-1- and TNF-alpha-neutralizing antibodies [3].
• Regulation of pulmonary Pseudomonas aeruginosa infection by the transcriptional repressor Gfi1 [3].
• Gfi1(-/-) mice show a very strong systemic response to the endotoxin LPS and die rapidly within 36 h with symptoms of septic shock [4].

Psychiatry related information on Gfi1

• Moreover, the combinatorial expression of Pim-1 and Gfi-1 leads to accelerated development of T-cell lymphoma with a mean latency period of 114 days [5].

High impact information on Gfi1

• Deletion of the AXH domain abolishes the effects of glutamine-expanded hAtx-1 on Senseless/Gfi-1 [6].
• Similarly, overexpression of wild-type and glutamine-expanded hAtx-1 reduces Gfi-1 levels in Purkinje cells [6].
• Previous experiments have shown that Gfi1 is involved in T-cell lymphomagenesis and in the development of T-cell progenitors [2].
• We conclude that Gfi1 influences the differentiation of myeloid precursors into granulocytes or monocytes and acts in limiting the inflammatory immune response [2].
• Here we show that Gfi1 is also expressed outside the lymphoid system in granulocytes and activated macrophages, cells that mediate innate immunity (that is, non-specific immunity) [2].

Biological context of Gfi1

• Mice lacking Gfi1 show reduced thymic cellularity due to an increased cell death rate, lack of proliferation, and a differentiation block in the very early uncommitted CD4-/CD8-/c-Kit+ cytokine-dependent T cell progenitors that have not yet initiated VDJ recombination [7].
• In addition, Gfi1-deficient mice show increased major histocompatibility complex class I-restricted positive selection and develop significantly more CD8+ cells suggesting a requirement of Gfi1 for a correct CD4/CD8 lineage decision [7].
• The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival [8].
• Furthermore, Gfi1 mutant mice lose all cochlear hair cells just prior to and soon after birth through apoptosis [8].
• We show that Gfi1 mRNA is expressed in many areas that give rise to neuronal cells during embryonic development in mouse, and that Gfi1 protein has a more restricted expression pattern [8].

Anatomical context of Gfi1

• The transcriptional repressor Gfi1 affects development of early, uncommitted c-Kit+ T cell progenitors and CD4/CD8 lineage decision in the thymus [7].
• Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene [9].
• These results identify Gfi1 as the first downstream target of a hair cell specific transcription factor and suggest that outer hair cell degeneration in Pou4f3 mutants is largely or entirely a result of the loss of expression of Gfi1 [9].
• The loss of Gfi1 results in outer hair cell degeneration, which appears comparable to that observed in Pou4f3 mutants [9].
• Although Gfi1-deficient mice initially specify inner ear hair cells, these hair cells are disorganized in both the vestibule and cochlea [8].

Associations of Gfi1 with chemical compounds

• Using transgenic mice that constitutively express the zinc finger protein Gfi-1 and the serine/threonine kinase Pim-1, we found that the levels of both proteins are important for the correct development of DP cells from DN precursors at the stage where 'beta-selection' occurs [10].
• The Gfi-1 binding site, TAAATCAC(A/T)GCA, was defined via random oligonucleotide selection utilizing a bacterially expressed glutathione S-transferase-Gfi-1 fusion protein [11].
• After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis [12].

Physical interactions of Gfi1

• The repression is direct and depends on several Gfi-1-binding sites in the p53-inducible Bax promoter [13].

Regulatory relationships of Gfi1

• Alveolar macrophages but not airway epithelial cells from Gfi1(-/-) mice were found to be responsible for the enhanced cytokine production [4].
• The Gfi-1 protooncoprotein represses Bax expression and inhibits T-cell death [13].
• Analysis of the CD25(+)/CD44(-,lo) DN subpopulation from these animals revealed that Gfi-1 inhibits and Pim-1 promotes the development of larger beta-selected cycling cells ('L subset') from smaller resting cells ('E subset') within this subpopulation [10].
• Here we show that overexpression of Gfi-1 also inhibits cell death induced by cultivation of IL-2-dependent T-cell lines in IL-2-deficient media [13].

Other interactions of Gfi1

• To validate this result, we performed semi-quantitative RT-PCR and in situ hybridizations for Gfi1 on wild-type and Pou4f3 mutant mice [9].
• However, neither Gfi1 nor Gfi1b has been implicated in nervous system development, even though their invertebrate homologues, senseless in Drosophila and pag-3 in C. elegans are expressed and required in the nervous system [8].
• Evi5 thus encodes a gene separate from Gfi1 that may also be involved in T-cell disease [14].
• Proviral activation of the Pim and Myc genes but not the Gfi1 gene were frequently observed in these tumors [15].
• Gfi1 was first identified as causing interleukin 2-independent growth in T cells and lymphomagenesis in mice [8].

Analytical, diagnostic and therapeutic context of Gfi1

• Transplantation of Gfi1-deficient bone marrow results in a compromised radioprotection and lower numbers of colony forming units in the spleen of wild-type recipients [16].
• Pharmacological inhibition of apoptosis in wild-type mice by intravenous injection of the broad-spectrum caspase inhibitor zVAD-cmk mimicked the phenotype of Gfi1-deficient mice and resulted in a profound sensitization of mice to P. aeruginosa, an increased release of cytokines, sepsis and death of the animals [3].
• Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPalpha, neutrophil elastase, and Gfi1 itself [17].
• Using PCR, a Gfi-1 homologous cDNA (mdGfi-1) was cloned from the house fly, Musca domestica [18].
• Recent gene targeting experiments and mutational screening in humans have revealed an essential role for Gfi-1 and Gfi-1B in hematopoiesis [19].

References