A Diffusible Factor Which Sustains Contact Inhibition of Replication

Abstract

Confluent 3T3 cultures make and release into the medium a diffusible factor which sustains the state of contact inhibition of replication. Evidence is given that the factor is a specific and reversible inhibitor of the RNA synthesis which precedes cellular replication.

Effect of Adenosine 3'-5'-Cyclic Monophosphate on Cell Proliferation

“…This partial release from growth inhibition by refeeding has been demonstrated before (34,36) and is thought to be due to a macromolecular substance in fresh serum which desensitizes a small percentage of cells to the inhibitory effects of cell contact (34) . The macromolecule involved appears to be depleted from fresh medium after incubation on confluent cultures for 2 days, as such depleted medium (contact-inhibited medium) had no stimulatory effect on confluent cultures, even when replenished with vitamins and amino acids ( Fig.…”

A Diffusible Factor Restoring Contact Inhibition of Growth to Malignant Melanocytes

“…It was considered possible that such hypothetical inhibitors might be transferred directly from cell to cell in a manner analogous to that already shown to occur Nor is the specificity of contact-inhibitory factor known with respect to other malignant cell types. It clearly differs from the diffusible extracellular factor reported from another aneuploid, contact-inhibited cell line, 3T3 (22) …”

Density-dependent regulation of cell growth: An example of a cell-cell recognition phenomenon

“…There are at least two distinct entities in the membrane bound class: the GIP described by Bunge et al [8] and the FGRF described by Natraj and Datta [14,53]. The data concerning the soluble factors suggest at least two classes for those molecules, one being the transport regulatory factors described by Yeh and Fisher [102] and Pariser and Cunningham [60], and the other being the growth inhibitory factors described by Harel et al [33] and Steck et al [81]. If all these factors survive the test of time and are shown to be truly independent entities, then their existence suggests that cells can respond to a number of different signals for inhibition of cell growth, and all may be utilized during the normal growth of a cell.…”

“…It is also not known if this factor, which is released by the cells, is normally a membrane-bound factor or a soluble one, and if membrane bound, the nature of the signal that causes it to be released into the medium is not known. This soluble factor described by Harel et al [33] and Steck et al [81] may be the same as the one described by Yeh and Fisher [102]; the former factor is low molecular weight (less than 10,000 daltons), but its heat sensitivity was not examined. GIP is clearly different from these factors; GIP is heat sensitive, undialyzable (10,000 mol wt cut-off), is not released into medium in active form (D. Raben, un-published observations'), and has no requirement for a minimum target density (see ref.…”

“…These factors all appear to be distinct from the growth inhibitory protein (GIP) described above, and their properties are discussed below. The first report was a factor described by Yeh and Fisher [102] in 1969. This factor was released from 3T3 cells and appeared to reduce the rate of RNA synthesis in neighboring cells, which effectively will keep cells in a quiescent state.…”