Cell growth
Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis is greater than the overall rate of cellular degradation.
Cell growth is not to be confused with cell division or the cell cycle, which are distinct processes that can occur alongside cell growth during the process of cell proliferation, where a cell, known as the mother cell, grows and divides to produce two daughter cells. Importantly, cell growth and cell division can also occur independently of one another. During early embryonic development, cell divisions occur repeatedly without cell growth. Conversely, some cells can grow without cell division or without any progression of the cell cycle, such as growth of neurons during axonal pathfinding in nervous system development.
In multicellular organisms, tissue growth rarely occurs solely through cell growth without cell division, but most often occurs through cell proliferation. This is because a single cell with only one copy of the genome in the cell nucleus can perform biosynthesis and thus undergo cell growth at only half the rate of two cells. Hence, two cells grow at twice the rate of a single cell, and four cells grow at 4-times the rate of a single cell. This principle leads to an exponential increase of tissue growth rate during cell proliferation, owing to the exponential increase in cell number.
Cell size depends on both cell growth and cell division, with a disproportionate increase in the rate of cell growth leading to production of larger cells and a disproportionate increase in the rate of cell division leading to production of many smaller cells. Cell proliferation typically involves balanced cell growth and cell division rates that maintain a roughly constant cell size in the exponentially proliferating population of cells.
Some special cells can grow to very large sizes via an unusual endoreplication cell cycle in which the genome is replicated during S-phase but there is no subsequent mitosis or cell division. These large endoreplicating cells have many copies of the genome, so are highly polyploid.
Oocytes can be unusually large cells in species for which embryonic development takes place away from the mother's body within an egg that is laid externally. The large size of some eggs can be achieved either by pumping in cytosolic components from adjacent cells through cytoplasmic bridges named ring canals or by internalisation of nutrient storage granules by endocytosis.
Mechanisms of cell growth control
can grow by increasing the overall rate of cellular biosynthesis such that production of biomolecules exceeds the overall rate of cellular degradation of biomolecules via the proteasome, lysosome or autophagy.Biosynthesis of biomolecules is initiated by expression of genes which encode RNAs and/or proteins, including enzymes that catalyse synthesis of lipids and carbohydrates.
Individual genes are generally expressed via transcription into messenger RNA and translation into proteins, and the expression of each gene occurs to various different levels in a cell-type specific fashion.
To drive cell growth, the global rate of gene expression can be increased by enhancing the overall rate of transcription by RNA polymerase II or the overall rate of mRNA translation into protein by increasing the abundance of ribosomes and tRNA, whose biogenesis depends on RNA polymerase I and RNA polymerase III. The Myc transcription factor is an example of a regulatory protein that can induce the overall activity of RNA polymerase I, RNA polymerase II and RNA polymerase III to drive global transcription and translation and thereby cell growth.
In addition, the activity of individual ribosomes can be increased to boost the global efficiency of mRNA translation via regulation of translation initiation factors, including the 'translational elongation initiation factor 4E' complex, which binds to and caps the 5' end of mRNAs. The protein TOR, part of the TORC1 complex, is an important upstream regulator of translation initiation as well as ribosome biogenesis. TOR is a serine/threonine kinase that can directly phosphorylate and inactivate a general inhibitor of eIF4E, named 4E-binding protein, to promote translation efficiency. TOR also directly phosphorylates and activates the ribosomal protein S6-kinase, which promotes ribosome biogenesis.
To inhibit cell growth, the global rate of gene expression can be decreased or the global rate of biomolecular degradation can be increased by increasing the rate of autophagy. TOR normally directly inhibits the function of the autophagy inducing kinase Atg1/ULK1. Thus, reducing TOR activity both reduces the global rate of translation and increases the extent of autophagy to reduce cell growth.
Cell growth regulation in animals
Many of the signal molecules that control of cellular growth are called growth factors, many of which induce signal transduction via the PI3K/AKT/mTOR pathway, which includes upstream lipid kinase PI3K and the downstream serine/threonine protein kinase Akt, which is able to activate another protein kinase TOR, which promotes translation and inhibits autophagy to drive cell growth.Nutrient availability influences production of growth factors of the Insulin/IGF-1 family, which circulate as hormones in animals to activate the PI3K/AKT/mTOR pathway in cells to promote TOR activity so that when animals are well fed they will grow rapidly and when they are not able to receive sufficient nutrients they will reduce their growth rate. Recently it has been also demonstrated that cellular bicarbonate metabolism, which is responsible for cell growth, can be regulated by mTORC1 signaling.
In addition, the availability of amino acids to individual cells also directly promotes TOR activity, although this mode of regulation is more important in single-celled organisms than in multicellular organisms such as animals that always maintain an abundance of amino acids in circulation.
One disputed theory proposes that many different mammalian cells undergo size-dependent transitions during the cell cycle. These transitions are controlled by the cyclin-dependent kinase Cdk1. Though the proteins that control Cdk1 are well understood, their connection to mechanisms monitoring cell size remains elusive.
A postulated model for mammalian size control situates mass as the driving force of the cell cycle. A cell is unable to grow to an abnormally large size because at a certain cell size or cell mass, the S phase is initiated. The S phase starts the sequence of events leading to mitosis and cytokinesis. A cell is unable to get too small because the later cell cycle events, such as S, G2, and M, are delayed until mass increases sufficiently to begin S phase.
Cell populations
Cell populations go through a particular type of exponential growth called doubling or cell proliferation. Thus, each generation of cells should be twice as numerous as the previous generation. However, the number of generations only gives a maximum figure as not all cells survive in each generation. Cells can reproduce in the stage of Mitosis, where they double and split into two genetically equal cells.Cell size
Cell size is highly variable among organisms, with some algae such as Caulerpa taxifolia being a single cell several meters in length. Plant cells are much larger than animal cells, and protists such as Paramecium can be 330 μm long, while a typical human cell might be 10 μm. How these cells "decide" how big they should be before dividing is an open question. Chemical gradients are known to be partly responsible, and it is hypothesized that mechanical stress detection by cytoskeletal structures is involved. Work on the topic generally requires an organism whose cell cycle is well-characterized.Yeast cell size regulation
The relationship between cell size and cell division has been extensively studied in yeast. For some cells, there is a mechanism by which cell division is not initiated until a cell has reached a certain size. If the nutrient supply is restricted, and the rate of increase in cell size is slowed, the time period between cell divisions is increased. Yeast cell-size mutants were isolated that begin cell division before reaching a normal/regular size.Wee1 protein is a tyrosine kinase that normally phosphorylates the Cdc2 cell cycle regulatory protein, a cyclin-dependent kinase, on a tyrosine residue. Cdc2 drives entry into mitosis by phosphorylating a wide range of targets. This covalent modification of the molecular structure of Cdc2 inhibits the enzymatic activity of Cdc2 and prevents cell division. Wee1 acts to keep Cdc2 inactive during early G2 when cells are still small. When cells have reached sufficient size during G2, the phosphatase Cdc25 removes the inhibitory phosphorylation, and thus activates Cdc2 to allow mitotic entry. A balance of Wee1 and Cdc25 activity with changes in cell size is coordinated by the mitotic entry control system. It has been shown in Wee1 mutants, cells with weakened Wee1 activity, that Cdc2 becomes active when the cell is smaller. Thus, mitosis occurs before the yeast reach their normal size. This suggests that cell division may be regulated in part by dilution of Wee1 protein in cells as they grow larger.
Linking Cdr2 to Wee1
The protein kinase Cdr2 and the Cdr2-related kinase Cdr1 are localized to a band of cortical nodes in the middle of interphase cells. After entry into mitosis, cytokinesis factors such as myosin II are recruited to similar nodes; these nodes eventually condense to form the cytokinetic ring. A previously uncharacterized protein, Blt1, was found to colocalize with Cdr2 in the medial interphase nodes. Blt1 knockout cells had increased length at division, which is consistent with a delay in mitotic entry. This finding connects a physical location, a band of cortical nodes, with factors that have been shown to directly regulate mitotic entry, namely Cdr1, Cdr2, and Blt1.Further experimentation with GFP-tagged proteins and mutant proteins indicates that the medial cortical nodes are formed by the ordered, Cdr2-dependent assembly of multiple interacting proteins during interphase. Cdr2 is at the top of this hierarchy and works upstream of Cdr1 and Blt1. Mitosis is promoted by the negative regulation of Wee1 by Cdr2. It has also been shown that Cdr2 recruits Wee1 to the medial cortical node. The mechanism of this recruitment has yet to be discovered. A Cdr2 kinase mutant, which is able to localize properly despite a loss of function in phosphorylation, disrupts the recruitment of Wee1 to the medial cortex and delays entry into mitosis. Thus, Wee1 localizes with its inhibitory network, which demonstrates that mitosis is controlled through Cdr2-dependent negative regulation of Wee1 at the medial cortical nodes.