Differentiation-inducing factor

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Differentiation-inducing factor 1.svg
Differentiation-inducing factor 1
Differentiation-inducing factor 2.svg
Differentiation-inducing factor 2
Differentiation-inducing factor 3.svg
Differentiation-inducing factor 3

Differentiation-inducing factor (DIF) is one of a class of effector molecules that induce changes in cell chemistry, inhibiting growth and promoting differentiation of cell type. This name has been given to several factors before it was clear if they were the same or different effectors. DIFs have garnered interest with their potential tumor inhibiting properties. [1] DIFs have also been used to help regulate plant growth.

Contents

Differentiation-inducing factors 1-3

Initial studies

Dictyostelium discoideum has been used since the 1940s to study cellular and developmental biology. [2] It is well-suited for this research because it only develops two types of cells (stalk and spore) during morphogenesis. Each cell type has a distinct physical origin within the organism; pre-stalk cells coming from the anterior side and pre-spore cells from the posterior. Early evidence showed the differentiation of dense patches of pre-stalk cells were induced by cyclic AMP (cAMP) along with "a factor" that was likely low in molecular weight and able to diffuse across membranes. [3] The structures for DIF-1, DIF-2, and DIF-3 were identified as these factors for stalk differentiation and subsequently synthesized to further research into implications for developmental biology. [4] [5] DIFs 1-3 are chlorinated hexaphenones (phenylalkan-1-ones, with chloro, hydroxy and methoxy substitution on the benzene ring), and have been isolated from Dictyostelium discoideum slime mold.

Some research has shown that they have a role in controlling chemotaxis of Dictyostelium discoideum , too. DIF-1 and DIF-3 are related in structure and function. DIF-3 is formed from the first step in the breakdown of DIF-1. In this state DIF-3 only performs about 3.5% as much of the activity of its predecessor. DIF-2 is unrelated to DIFs -1 and -3, but it works 40% as well as DIF-1 does to induce differentiation in stalk cells. Despite this similarity in function during differentiation, DIFs -1 and -2 act very differently in chemotactic movement of the cells toward cAMP. DIF-1 has a slight inhibitory effect on movement of starved cells toward cAMP, while DIF-2 has a strong positive effect of movement of these cells toward cAMP. These effects are thought to be carried out through phosphodiesterase activations that impact cGMP production to impact chemotaxis. [6] An increase in chemotaxis can be related to malignant migration of cancer cells.

Anti-tumor properties

Investigation into the anti-tumor properties of DIFs have followed one main line; the disruption of a pathway necessary for the cancer's uncontrolled growth reducing its proliferative ability. As mentioned above, the ability of DIF-1 to decrease movement of proliferating cells toward sources of energy could serve as an anti-tumor property. In another example, DIF-1 has been shown to reduce the proliferation of gastric cancer cells via upregulation of the MEK-ERK-dependent pathway. [7] Other studies have shown how complicated the anti-tumor interactions of DIFs may be, especially when considering the indirect impacts DIFs have on target molecules. For instance, DIF-like molecules have been shown to inhibit cell growth and bring about cell death through uncoupling in mitochondria. [8]

Expanding uses for DIF-like molecules

Derivatives of DIF-1 and DIF-3 have already been investigated with promising initial results. One group of derivatives yielded two DIF-1-like compounds that were effective in suppression of IL-2 production which could be helpful in controlling septic responses and other infections. [9]

Running List of DIF and DIF-like molecule effects

Related Research Articles

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Slime mold or slime mould is an informal name given to a polyphyletic assemblage of unrelated eukaryotic organisms in the Stramenopiles, Rhizaria, Discoba, Amoebozoa and Holomycota clades. Most are microscopic; those in the Myxogastria form larger plasmodial slime molds visible to the naked eye. The slime mold life cycle includes a free-living single-celled stage and the formation of spores. Spores are often produced in macroscopic multicellular or multinucleate fruiting bodies that may be formed through aggregation or fusion; aggregation is driven by chemical signals called acrasins. Slime molds contribute to the decomposition of dead vegetation; some are parasitic.

<span class="mw-page-title-main">Dictyostelid</span> Group of slime moulds

The dictyostelids or cellular slime molds are a group of slime molds or social amoebae.

<span class="mw-page-title-main">Mycetozoa</span> Infraphylum of protists

Mycetozoa is a polyphyletic grouping of slime molds. It was originally thought to be a monophyletic clade, but recently it was discovered that protostelia are a polyphyletic group within Conosa.

<i>Dictyostelium</i> Genus of slime molds

Dictyostelium is a genus of single- and multi-celled eukaryotic, phagotrophic bacterivores. Though they are Protista and in no way fungal, they traditionally are known as "slime molds". They are present in most terrestrial ecosystems as a normal and often abundant component of the soil microflora, and play an important role in the maintenance of balanced bacterial populations in soils.

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<span class="mw-page-title-main">CYR61</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">IER3</span> Protein-coding gene in the species Homo sapiens

Radiation-inducible immediate-early gene IEX-1 is a protein that in humans is encoded by the IER3 gene.

<i>Dictyostelium discoideum</i> Species of slime mould

Dictyostelium discoideum is a species of soil-dwelling amoeba belonging to the phylum Amoebozoa, infraphylum Mycetozoa. Commonly referred to as slime mold, D. discoideum is a eukaryote that transitions from a collection of unicellular amoebae into a multicellular slug and then into a fruiting body within its lifetime. Its unique asexual life cycle consists of four stages: vegetative, aggregation, migration, and culmination. The life cycle of D. discoideum is relatively short, which allows for timely viewing of all stages. The cells involved in the life cycle undergo movement, chemical signaling, and development, which are applicable to human cancer research. The simplicity of its life cycle makes D. discoideum a valuable model organism to study genetic, cellular, and biochemical processes in other organisms.

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<span class="mw-page-title-main">Sporulation in Bacillus subtilis</span>

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References

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  8. 1 2 Kubohara, Yuzuru; Kikuchi, Haruhisa; Matsuo, Yusuke; Oshima, Yoshiteru; Homma, Yoshimi (2013-08-15). "Mitochondria Are the Target Organelle of Differentiation-Inducing Factor-3, an Anti-Tumor Agent Isolated from Dictyostelium Discoideum". PLOS ONE. 8 (8): e72118. Bibcode:2013PLoSO...872118K. doi: 10.1371/journal.pone.0072118 . PMC   3744471 . PMID   23977224.
  9. 1 2 Nguyen, Van Hai; Kikuchi, Haruhisa; Kubohara, Yuzuru; Takahashi, Katsunori; Katou, Yasuhiro; Oshima, Yoshiteru (2015-08-01). "Development of novel DIF-1 derivatives that selectively suppress innate immune responses". Bioorganic & Medicinal Chemistry. 23 (15): 4311–4315. doi:10.1016/j.bmc.2015.06.027. PMID   26122773.
  10. Sugden, Chris; Urbaniak, Michael D.; Araki, Tsuyoshi; Williams, Jeffrey G. (2015-02-15). "The Dictyostelium prestalk inducer differentiation-inducing factor-1 (DIF-1) triggers unexpectedly complex global phosphorylation changes". Molecular Biology of the Cell. 26 (4): 805–820. doi:10.1091/mbc.E14-08-1319. ISSN   1939-4586. PMC   4325849 . PMID   25518940.
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