Phosphoinositide 3-Kinase Activation Regulates Cell Division Time by Coordinated Control of Cell Mass and Cell Cycle Progression Rate

Abstract

Cells must increase their mass in coordination with cell cycle progression to ensure that their size and macromolecular composition remain constant for any given proliferation rate. To this end, growth factors activate early signaling cascades that simultaneously promote cell mass increase and induce cell cycle entry. Nonetheless, the mechanism that controls the concerted regulation of cell growth and cell cycle entry in mammals remains unknown. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B pathway regulates cell cycle entry by inactivating forkhead transcription factors and promoting cyclin D synthesis. PI3K/protein kinase Bderived signals also affect activation of p70 S6 kinase and the mammalian target of rapamycin, enzymes involved in cell growth control. We previously showed that enhancement of PI3K activation accelerates cell cycle entry, whereas reduction of PI3K activation retarded this process. Here we examined whether expression of different PI3K mutants affects cell growth during cell division. We show that diminishing or enhancing the magnitude of PI3K activation in a transient manner reduces or increases, respectively, the protein synthesis rate. Alteration of cell growth and cell cycle entry by PI3K forms appears to be concerted, because it results in lengthening or shortening of cell division time without altering cell size. In support of a central role for PI3K in growth control, expression of a deregulated, constitutive active PI3K mutant affects p70 S6 kinase and mammalian target of rapamycin activities and increases cell size. Together, the results show that transient PI3K activation regulates cell growth and cell cycle in a coordinated manner, which in turn controls cell division time.

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

“…Consistently, reduction of mTOR, raptor, or GbL expression with RNAi also reduces cell size (Kim et al, 2002;Kim et al, 2003). Overexpression of PI3K or Akt increases cell size in a rapamycin-sensitive manner, indicating that the ability of the PI3K/Akt pathway to drive cell growth is mTOR dependent (Alvarez et al, 2003;Faridi et al, 2003). Overexpression of S6K1 or eIF4E also increases cell size, while overexpression of a dominantly acting mutant of 4E-BP1 decreases cell size .…”

“…The role of mTOR in coordinating cell growth and cell cycle progression differs from the proposed role of PI3K as such a coordinator (Alvarez et al, 2003). While the PI3K pathway promotes cell growth in an mTORdependent manner, it also is able to accelerate cell cycle progression, cell division, and cell proliferation under optimal conditions, likely via mTOR-independent pathways (Alvarez et al, 2003).…”

“…While the PI3K pathway promotes cell growth in an mTORdependent manner, it also is able to accelerate cell cycle progression, cell division, and cell proliferation under optimal conditions, likely via mTOR-independent pathways (Alvarez et al, 2003). More mechanistically speaking, the PI3K/Akt pathway is reported to control directly the phosphorylation and stability of cyclin D1 (Diehl et al, 1998), and the phosphorylation and function of the cdk inhibitory protein p21 (Rossig et al, 2001;Zhou et al, 2001).…”

p85 regulatory subunit of PI3K mediates cAMP–PKA and estrogens biological effects on growth and survival

“…For example, constitutive expression of p110a increases cell mass and size by stimulating the biosynthetic capacity of the cells. However, if not restrained, p110 activity impairs exit from the cell cycle (Alvarez et al, 2003). We suggest that Ras-PI3K signals regulate the length of G1 phase.…”

The coordination of signaling during Fc receptor-mediated phagocytosis

“…Phagocytes may regulate phagosome formation based on their ability to accommodate such displacements. PI-3K has been implicated in cell-size regulation [115,116]. The PI-3K dependence of phagocytosis could indicate a checkpoint related to cell size, which constrains the size of the particle that can be internalized.…”