Cell proliferation is fundamental to development, maintenance of steady-state tissue homeostasis, and replacement of dead or damaged cells. The key elements of cellular proliferation are accurate DNA replication accompanied by the coordinated synthesis of all other cellular constituents, followed by equal apportionment of DNA and other cellular constituents (e.g., organelles) to daughter cells through mitosis and cytokinesis.

The sequence of events that results in cell division is called the cell cycle; it consists of G1 (presynthetic growth), S (DNA synthesis), G2 (premitotic growth), and M (mitotic) phases (Fig. 1). Quiescent cells that are not actively cycling are said to be in the G0 state. Cells can enter G1 either from the G0 quiescent cell pool, or after completing a round of mitosis, as for continuously replicating cells. Each stage requires completion of the previous step, as well as activation of necessary factors (see later); nonfidelity of DNA replication, or cofactor deficiency result in arrest at the various transition points.

Fig1. Cell cycle landmarks. The figure shows the cell cycle phases (G0, G1, G2, S, and M), the location of the G1 restriction point, and the G1/S and G2/M cell cycle checkpoints. Cells from labile tissues such as the epidermis and the GI tract may cycle continuously; stable cells such as hepatocytes are quiescent but can enter the cell cycle; permanent cells such as neurons and cardiac myocytes have lost the capacity to proliferate. (Modified from Pollard TD, Earnshaw WC: Cell Biology. Philadelphia, Saunders, 2002.)

The cell cycle is regulated by activators and inhibitors. Cell cycle progression is driven by proteins called cyclins— named for the cyclic nature of their production and degradation—and cyclin-associated enzymes called cyclindependent kinases (CDKs) (Fig. 2). CDKs acquire the ability to phosphorylate protein substrates (i.e., kinase activity) by forming complexes with the relevant cyclins. Transiently increased synthesis of a particular cyclin leads to increased kinase activity of the appropriate CDK binding partner; as the CDK completes its round of phosphorylation, the associated cyclin is degraded and the CDK activity abates. Thus, as cyclin levels rise and fall, the activity of associated CDKs likewise wax and wane.

Fig2. Role of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors in regulating the cell cycle. The shaded arrows represent the phases of the cell cycle during which specific cyclin-CDK complexes are active. As illustrated, cyclin D CDK4, cyclin D-CDK6, and cyclin E-CDK2 regulate the G1-to-S transition by phosphorylating the Rb protein (pRb). Cyclin A-CDK2 and cyclin A-CDK1 are active in the S phase. Cyclin B-CDK1 is essential for the G2-to-M transition. Two families of CDK inhibitors can block activity of CDKs and progression through the cell cycle. The so-called INK4 inhibitors, composed of p16, p15, p18, and p19, act on cyclin D-CDK4 and cyclin D-CDK6. The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.

More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs. The cell cycle can thus be conceived as a relay race in which each leg is regulated by a distinct set of cyclins: as one collection of cyclins leaves the track, the next set takes over.

Embedded in the cell cycle are surveillance mechanisms primed to sense DNA or chromosomal damage. These quality control checkpoints ensure that cells with genetic imperfections do not complete replication. Thus, the G1-S checkpoint monitors the integrity of DNA before irreversibly committing cellular resources to DNA replication. Later in the cell cycle, the G2-M restriction point ensures that there has been accurate genetic replication before the cell actually divides. When cells do detect DNA irregularities, checkpoint activation delays cell cycle progression and triggers DNA repair mechanisms. If the genetic derangement is too severe to be repaired, the cells will undergo apoptosis; alternatively, they may enter a nonreplicative state called senescence—primarily through p53- dependent mechanisms (see later).

Enforcing the cell cycle checkpoints is the job of CDK inhibitors (CDKIs); they accomplish this by modulating CDK-cyclin complex activity. There are several different CDKIs:

• One family—composed of three proteins called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C)— broadly inhibits multiple CDKs.

• The other family of CDKI proteins has selective effects on cyclin CDK4 and cyclin CDK6; these proteins are called p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D).

Defective CDKI checkpoint proteins allow cells with damaged DNA to divide, resulting in mutated daughter cells with the potential of developing into malignant tumors.

An equally important aspect of cell growth and division is the biosynthesis of other cellular components needed to make two daughter cells, such as membranes and organelles. At the same time that growth factor receptor signaling stimulates cell cycle progression, it also activates events that promote changes in cellular metabolism that support growth. Chief among these is the Warburg effect, mentioned earlier, which is marked by increased cellular uptake of glucose and glutamine, increased glycolysis, and (counter- intuitively) decreased oxidative phoshorylation. These changes become fixed in cancer cells and are discussed in greater detail in Chapter 7.

اخر الاخبار

اخبار العتبة العباسية المقدسة

وزارة التعليم العالي تكرم جامعة العميد لحصولها على جائزة المكتبة الأكاديمية المتميزة

جمعية العميد تناقش استعداداتها لانطلاق فعاليات المؤتمر العلمي الرابع لإحياء تراث أمير المؤمنين (عليه السلام)

أكاديمية التطوير الإداري تواصل برنامج الخطة الخمسينية لعدد من ملاكات العتبة العباسية المقدسة

المجمع العلمي يواصل تقديم دورته التطويرية لعدد من الملاكات التربوية في الديوانية

المزيد

الآخبار الصحية

الرياضة وحدها لا تكفي.. كيف يؤثر الجلوس الطويل على الصحة؟

دراسة: بدائل السكر ليست آمنة على الكبد

تفاحة قبل النوم.. عادة بسيطة مفيدة أم خطر على الصحة؟

احذر مشاركتها مع الآخرين.. 3 أدوات شائعة قد تنقل أمراض خطيرة

المزيد

الآخبار التكنلوجية

الهنغاري لاسلو كراسناهوركاي يفوز بجائزة نوبل للآداب 2025

رسميا.. إعلان الفائز بجائزة نوبل للسلام لعام 2025

باحثون: تشات جي بي تي ونماذج الذكاء الاصطناعي يمكن "تسميمها"

عالمان في الأعصاب يرفعان دعوى قضائية ضد شركة آبل

المزيد

مواضيع ذات صلة

Stem Cells

Growth Factors and Receptors

Signal Transduction Pathways

Cell Signaling

Cellular Metabolism and Mitochondrial Function

Waste Disposal: Lysosomes and Proteasomes

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions

Plasma Membrane: Protection and Nutrient Acquisition

Cytoplasmic Structures in Prokaryotic Cell

Eukaryotic Cell Structure

Cell Differentiation