ReviewRegulation of G1 cell-cycle progression by oncogenes and tumor suppressor genes
Introduction
Cell proliferation is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. The somatic cell cycle is divided into an interphase, designated for cellular growth and DNA synthesis, and a mitotic phase, in which a single cell divides into two daughter cells. Interphase is further subdivided into two gap phases (G1 and G2) separated by a phase of DNA synthesis (S phase). However, the vast majority of cells in the human body exist in a non-dividing, terminally differentiated state. In contrast, stem cells exist in a resting G0 quiescent state. Upon appropriate external stimulation, G0 cells can enter the cell cycle into early G1, likewise cycling cells present in early G1 can exit into G0 when deprived of external growth stimulus [1].
Studies of tumor cell growth kinetics have revealed that at least three parameters are critical to tumor growth in vivo: first, the duration of a single cell cycle; second, the proportion of cells actively proliferating (known as the ‘growth fraction’); and third, the rate of cell loss as a result of death or apoptosis [2]. Surprisingly, the length of tumor cell cycles measured in vivo and in vitro are not significantly shorter than those of normal cells, suggesting that neoplastic cells are acquiring genetic alterations that either enhance the growth fraction and/or minimize cell loss, rather than simply decreasing the cell-cycle duration. Consequently, processes that govern cell-cycle entrance/exit and metabolism are perhaps more important to tumor growth than those events that regulate the rate of individual cell division. These ideas help to understand the consequences associated with alterations of the cell-cycle machinery during oncogenesis.
The point between the early G1 and late G1 phase passage that represents an irreversible commitment to undergo one cell division is termed the ‘restriction point’ [1]. Importantly, the restriction point divides the cell cycle into a growth factor dependent early G1 phase and growth factor independent phases from late G1 through mitosis [1]. Growth factor signaling determines whether early G1 phase cells transit the restriction point to undergo eventual cellular division or, because of insufficient signaling strength, exit the cell cycle, enter into G0. Thus, although overcoming growth factor signaling dependency is a major hurdle in the development of neoplastic disease, this requirement actually serves at least three significant purposes: first, avoidance of G0 exit; second, sustained metabolism; and third, transition across the restriction point into late G1 (Fig. 1). Surprisingly, the role and significance of growth-factor signaling required to avoid cell cycle exit and sustain metabolism during oncogenesis has been greatly overlooked in tumor biology studies.
Section snippets
The retinoblastoma protein family
Retinoblastoma (Rb) is a rare childhood malignancy that serves as the classic model for the loss of tumor suppressor function, namely pRb (Rb protein), in oncogenesis [3]. pRb is a key negative regulator at the restriction point. Surprisingly, with the exception of three relatively rare malignancies (retinoblastoma, osteosarcoma, and small cell lung carcinoma) [3], the overall rate of Rb mutation in the vast majority of human cancers is either extremely low or non-existent, suggesting that
Cyclin–Cdk complexes during G1
Although pRb is a negative regulator of early G1 cell-cycle progression, it is paradoxically regulated by the positive regulators of cell-cycle progression, namely cyclin–cdk complexes. Cyclin–cdk complexes are an evolutionarily conserved family of proline-dependent serine/threonine kinases [13]. During G1, two predominant cyclin–cdk complexes are active, namely cyclin D/cdk4/6, comprising three D-type cyclins (D1–3) and two different cdk subunits (cdk4 and cdk6), and cyclin E/cdk2 [13]. Cyclin
Cyclin–Cdk inhibitors during G0 and G1
Whereas cyclin–cdk complexes are key regulators of G1 cell cycle progression, evolution has added yet another layer of G1 cell cycle regulation in the form of cyclin–cdk inhibitory proteins. At present, two classes of G1 cyclin–cdk inhibitors, the INK4 and Cip/Kip families, operate in distinct fashions to regulate G1 cyclin–cdk complexes. The INK4 family, comprising p15, p16, p18 and p19 proteins, specifically bind monomeric cdk4/6 preventing cyclin D activation, whereas Cip/Kip family members,
Conclusions
An increasingly precise model for the regulation of G1 cell cycle progression in normal and neoplastic cells is emerging from recent genetic and biochemical studies that incorporate the observed physiological activities of cell-cycle regulatory proteins in normal and neoplastic cells (Fig. 2). These studies draw our attention to the significance of disrupting regulation of the G0 to early G1 progression in neoplasia, rather than those events involved directly in restriction point traversal.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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