Control of Cell Proliferation

Data gathered in animal models indicate that sex hormones control the number of cells in their target organs, first by inhibiting cell death and inducing cell proliferation (proliferative effect, Step I), and later by inhibiting further cell proliferation (shutoff effect, Step II).

Step I: The default state of prokaryotes, unicellular eukaryotes, and methaphyta is proliferation variation and motility. Based on an evolutionary perspective, we postulated that the default state of metazoan cells is also proliferation variation and motility. We proposed that proliferation is controlled negatively by specific plasma-borne inhibitors; hence, sex hormones would induce cell proliferation by neutralizing the effect of the plasma-borne inhibitors. To explore this hypothesis, we used estrogen target cells in a cell culture model. The serum-borne inhibitor of the proliferation of estrogen-target cells (estrocolyone-I) was identified as human serum albumin (HSA). Using recombinant truncated HSA peptides, we mapped the inhibitory activity to Domains I and II of the HSA molecule. Domain III lacked inhibitory activity.

Step II: These sex hormones also inhibit cell proliferation once the target organs achieve full development (proliferative shutoff effect). We selected cells expressing both the proliferative and inhibitory effect of hormones and obtained variants that expressed either the proliferative or the inhibitory effect. To explore Step II, we identified candidates that mediate the sex steroid-induced proliferative shutoff by means of subtracted libraries; the role of these candidates was tested using tetracycline-regulated expression of sense and antisense constructs. These studies revealed that APRIN, a gene located on chromosome 13 in the BRCA2-Rb1 locus, which seems to act as a chromatin regulator, mediates the androgen-induced shutoff effect in the prostate.

Recommended Reading –