Importantly, the non-secreting Th cells do not permanently upregulate IL-2R in the presence of Treg cells because the Treg cells suppress the paracrine IL-2 signal.

Treg cells can suppress prolonged IL-2 signaling in Th cells by inhibiting the strong initial IL-2 signal and the resulting upregulation of the high-affinity IL-2R.

In response to IL-2 uptake, Th cells and Treg cells upregulate CD25, the oc-subunit of the IL-2R.

Although IL-2 secreting Th cells upregulate CD25, Long and Adler [37] reported that they lack phosphorylated STAT5, a key intermediate in the IL-2R signal transduction cascade.

In the same experiment, other Th cells not secreting IL-2 also upregulate CD25 in response to IL-2, and in addition show fully functional signal transduction [5,37].

Non-secreting cells are assumed to upregulate IL-2R expression in response to IL-2 homogeneously at their cell surface.

Then, in response to the high IL-2 concentration resulting from paracrine signaling, IL-2R expression is upregulated in non-secreting cells (Fig 3E) and causes fast IL-2 uptake from the medium.

This inhomoge-neity in IL-2 concentration corresponds to receptor upregulation (activation) of non-secreting Th cells: IL-2Rhigh cells are found near the regions with high IL-2 concentration.

Although immediate early genes are typically rapidly upregulated , they may also be downregulated as is the case for JUN in AoSMC-FGFZ.

It has been previously demonstrated that in response to EGF stimulation a set of 23 mature miRNA show a rapid reduction in expression that upregulates a large number of target mRNAs in non-tumori-genic MCF-10A breast epithelial cells [12].

In contrast, mature hsa-mir-21 was previously found to be upregulated on EGF stimulation [12, 35, 40].

We also found MIR99AHG (host gene for hsa-mir-99a, hsa-let-7c and hsa-mir-125b2) and two other lncRNA whose locus contains miRNA to be similarly transiently upregulated in two or more datasets.

Known IEGs are significantly enriched in CAGE clusters assigned to particular signatures (those involving early but transient upregulation within 240 minutes which we term the early peak response) and show other biological features of interest.

However, the mRNA targets of a number of immediately downregulated mature miRNA in this data were found preferentially in early peak (transiently upregulated ) protein-coding genes in the independent, but matched CAGE dataset thus supporting the use of kinetic signatures to detect meaningful temporal patterns (with respect to known miRNA targets).

On the attenuation of the immediate-early response, detailed kinetic modelling of the transient upregulation of the Atf3 transcription factor (an inhibitor of Egr1) has concluded that, following induction, the mechanism whereby Atf3 is rapidly repressed is likely to involve newly-synthesised miRNA [13].

Significant upregulation of NAB2, TRIB1 and GEM was previously found in MCF7 cells following EGF and HRG treatment (see 81 Table in [3]) These genes may play a role in the attenuation of the immediate-early response in MCF7 cells.

However, excess HIFloc that has not been degraded (in hypoxic conditions) is transported into the nucleus, where it binds to its dimer ARNT / HIFIB and subsequently upregulates other genes that promote cell growth [55].

Moreover, one study discovered a reciprocal, positive relationship between IGF and HIFloc, with HIFloc upregulating mRNAs encoding for IGF2 and IGFBP, but not that of IGFI [62].

This study offers an explanation for the difficulties encountered by current drugs targeting IGFIR to reduce glioblastoma cell growth: a secondary mechanism that upregulates HIFloc.

The method builds on the concept of stable motif and its relation to finding attractors [41], and takes it much further by connecting stable motifs with a way to identify targets whose manipulation ( upregulation or downregulation) ensures the convergence of the system to an attractor of interest.

upregulation or downregulation of mRNA levels in a disease state with respect to a healthy state).

The network control method we propose here builds on the concept of stable motifs and its relation to (quasi)attractors [41] and takes it much further by connecting stable motifs with a way to identify targets whose manipulation ( upregulation or downregulation) ensures the convergence of the system to an attractor of interest.