Cell cycle: Regulatory events in G₁ → S transition of mammalian cells

Abstract

A cell divides into two daughter cells by progressing serially through the precisely controlled G1, S, GZ, and M phases of the cell cycle. The crossing of the G1/S border, which is marked by the initiation of DNA synthesis, represents commitment to division into two complete cells. Beyond this critical point no further external signals are required. We now have more comprehensive knowledge of the temporal sequence of systems at this key transition from G1 to S-growth factor responses, a cascade of kinase reactions, activation of cyclins and their associated kinases, and oncogene and tumor suppressor gene products. Furthermore, we know that the absolute requirement for calcium and the timing of events associated with calmodulin and the 68 kDa calmodulin-binding protein are consistent with overall Ca++/calmodulin control of all steps from the response to growth factors in G1 to DNA replication in S phase. We now have to sort out the inter-relationships of myriad control proteins and their relation to the Ca++/calmodulin-dependent controls-Which are causes? Which are effects? And which are parallel processes? The answers will be important, as they represent both a much deeper understanding of this key process of life and an important opportunity for improving therapeutic medicine.

Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP

“…The cell cycle progression is regulated by activation and inactivation in different classes of cyclins, cyclin dependent kinase (CDK) and other regulatory proteins. 37,38 It has been well documented that abnormal regulation in the expression and/or activation of cyclin, CDK and regulatory factors resulted in blockage of cell cycle progression and causing the programmed cell death. 39 The formation of p34 cdc2 /cyclin B complex is associated with G2/M phase transient and M-phase entrance.…”

Increased expression of the INK4a/ARF locus in polycythemia vera

“…[22][23][24][25][26] Inactivation of various cell proliferation-regulating proteins (such as the Rb, CDK, and CDK inhibitor proteins), due to gene deletions or mutations, results in enhanced cell generation. 24 The INK4a/ARF locus provides important CDK inhibitors that include p16 INK4a and p14 ARF (p19 ARF in the mouse).…”

Effect of nicotine on cerebellar granule neuron development

“…Intracellular Ca 2+ signals regulate cell entry into and exit from mitosis (Reddy, 1994). Cells deprived of Ca 2+ cannot progress through the G 1 /S phase of the cell cycle (Means & Rasmussen, 1988;Reddy, 1994). Although the specific mechanisms underlying trophic events following nAChR activation require further evaluation, this study provides evidence for a direct cholinergic role in neurogenesis.…”

“…For instance, in many in vitro studies, nAChR activation can increase cell proliferation, e.g., in a thymic cell line, lung cell carcinoma, subsets of normal and neoplastic cervical cells, neuroendocrine and vascular smooth muscle cells (Tominaga et al, 1989;Maneckjee & Minna, 1990;Quik et al, 1994;Strohschneider et al;1994;Waggoner & Wang, 1994;Carty et al, 1997). In contrast, several studies report that nicotine administration decreases rat brain DNA synthesis in several regions including the cerebellum McFarland et al, 1991;Slotkin et al, 1994), although one recent report suggests that increased numbers of mitotic neural cells are present in rat embryos exposed to nicotine in vitro (Roy et al, 1998).…”

“…For example, the proliferative effects of nicotine could be related to the high Ca 2+ permeability of nAChRs (Wong, 1995;Role & Berg, 1996;Berger et al, 1998). Intracellular Ca 2+ signals regulate cell entry into and exit from mitosis (Reddy, 1994). Cells deprived of Ca 2+ cannot progress through the G 1 /S phase of the cell cycle (Means & Rasmussen, 1988;Reddy, 1994).…”