The Cell Cycle

Abstract

The Oncologist Fundamentals of Cancer MedicineThe cell cycle is a highly ordered process that results in the duplication and transmission of genetic information from one cell generation to the next. During the process DNA must be accurately replicated and identical chromosomal copies distributed to two daughter cells. The cell cycle is divided into discrete phases: G 1 (gap 1) is the interval or gap between mitosis (M phase) and DNA synthesis (S phase). During G 1 the cell is subject to stimulation by extracellular mitogens and growth factors; in response to these stimuli, the cell passes through G 1 and proceeds with DNA synthesis in S phase; G 2 (gap 2) is the interval between the completion of DNA synthesis (S) and mitosis; M phase is marked by the generation of bipolar mitotic spindles, segregation of sister chromatids and cell division. The regulation of the cell cycle must ensure that the events in each phase are complete before moving to the next. Thus checkpoints for monitoring the integrity of DNA are strategically placed in late G 1 and at the G 2 /M interface to prevent progression and propagation of mutated or damaged cells. G 0 refers to cells that are quiescent (temporarily or permanently out of cycle). The normal cell is dependent on external stimuli (mitogens or growth factors) to move it out of G 0 and through the early part of G 1 . The cell responds to these external stimuli, communicated through a cascade of intracellular phosphorylations, by upregulating expression of the cyclins which associate with the cyclin-dependent kinases (CDKs). The time periods shown in Figure 1 are generic and only indicate the relative duration of each phase.The cell cycle is propelled by a series of protein kinases; these CDKs complex with their respective cyclin and, subsequently, are phosphorylated by an activating kinase. Cyclin is the regulatory unit and CDK is its catalytic partner.Cyclins, with their bound and activated CDKs, function during distinct stages of the cell cycle. As the name suggests, the level of each cyclin independently increases or decreases within the phases of the cycle. Cyclin/CDK complexes phosphorylate specific protein substrates to move the cell through the cycle with activation of DNA synthesis (in late G 1 and S), and formation of the structural components associated with mitosis (in late G 2 and M). The periodicity of the cyclins, mediated by their synthesis and subsequent proteolytic degradation, ensure the well-delineated transitions between cell cycle stages. Because errors encoded in the genome may result in defective clones, close monitoring of the cell cycle for abnormal Figure 1. The Cell Cycle-Times are relative.

Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells

“…The proliferative effects of CD1 relate to its control of G 1 transition in specific cell types (Arnold et al, 1991), and although it functions primarily by forming active complexes with CDK4 (Israels and Israels, 2000), CD1 can also act via mechanisms that are independent of CDK4 (Zwijsen et al, 1997;Knudsen et al, 1999;Bienvenu et al, 2001). Elevated CD1 in tumours can be achieved through different mechanisms including deregulated gene expression, mutations or amplifications (Weinberg, 1995).…”

“…CDK4 protein controls G 1 transition in cells as they progress through the cell cycle (Arnold et al, 1991) by associating with regulatory partners such as cyclin D1 (CD1) (also referered to as PRAD1, CCND1) (Motokura et al, 1991) to phosphorylate specific substrates such as retinoblastoma protein (Israels and Israels, 2000). However, whereas CDK4 is inhibited by its association with inhibitory protein such as p21 cip1/waf1 , the regulatory cyclin subunits are regulated at the level of expression and by protein stability as cells progress through the cell cycle (Guo et al, 2005).…”

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

“…Elevated levels of p27 induces G1 arrest (Sherr, 2000). To permit hyperphosphorylation of pRb and cell-cycle progression, the inhibitory influence of p27 is removed through hyperphosphorylation, ubiquitination and destruction within the proteasome (Vlach et al, 1997;Israels and Israels, 2000). Owing to the high signal levels of total pRb, phospho-pRb, p27 and phospho-p27 found in the buccal mucosa in Study A, and the fact that the expression and activation of these cell-cycle proteins appeared relatively tightly controlled, with the nuclear signal being largely 'on or off' (Figure 2B -E) allowing easier automated counting, we chose to explore these markers in more detail in Study B.…”

3.ALPHA.,23-Isopropylidenedioxyolean-12-en-27-oic Acid, a Triterpene Isolated from Aceriphyllum rossii, Induces Apoptosis in Human Cervical Cancer HeLa Cells through Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

“…On the other hand, various studies suggested that caspase-8 is not only activated in the death receptor pathway, but can be also activated independently of death receptors. 26) In these previous studies, caspase-8 activation was found to be triggered by a caspase-3-mediated feedback amplification loop, and caspase-8 was proposed to act as an executioner caspase, rather than as an initiator caspase, in the death receptor-independent activation pathway. In our study, IPA did not influence the protein levels of Fas and TNFR1 (data not shown).…”