Differentiation-inducing factor

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Differentiation-inducing factor 1
Differentiation-inducing factor 2
Differentiation-inducing factor 3

Differentiation-inducing factor (DIF) is one of a class of

tumor inhibiting properties.[1]
DIFs have also been used to help regulate plant growth.

Differentiation-inducing factors 1-3

Initial studies

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

More recent focus has been on the potential therapeutic effects 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

  • Inhibit proliferation of cancer cells (leukemia, cervical, gastric, and colon) (DIF -1 and/or -3)
  • Reduces expression of Cyclin D mRNA and increases its degradation (DIF -1 and -3)
  • Inhibition of ERK and STAT3 signaling[7] (DIF -1)
  • Inhibition of PAK1 activity in breast cancer cells (DIF-3 derivative)
  • Suppression of IL-2 production[9] (DIF-1 derivatives)
  • Phosphorylation and dephosphorylation changes[10] (DIF-1)
  • Uncoupling in mitochondria[8] (DIF-3)
  • Inhibits PDE1[11](DIF-1)

References

  1. PMID 9240452
    .
  2. ^ Raper, K. B. J., Elisha Mitchell Scientific Soc., 56, 241–282 (1940).
  3. S2CID 2730246
    .
  4. PMID 3223901
    .
  5. PMID 3355503
    .
  6. PMID 19684855
    .
  7. ^
    PMID 12555068
    .
  8. ^
    PMID 23977224
    .
  9. ^
    PMID 26122773
    .
  10. PMID 25518940
    .
  11. ^ 11
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