PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “multicellular coordination”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources

Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila.

Multicellular organisms must integrate growth and differentiation precisely to pattern complex tissues. Despite great progress in understanding how different cell fates are induced, it is poorly understood how differentiation decisions are temporally regulated. In a screen for patterning mutants, we isolated alleles of tsc1, a component of the insulin receptor (InR) growth control pathway. We find that loss of tsc1 disrupts patterning due to a loss of temporal control of differentiation. tsc1 controls the timing of differentiation downstream or in parallel to the RAS/MAPK pathway. Examination of InR, PI3K, PTEN, Tor, Rheb, and S6 kinase mutants demonstrates that increased InR signaling leads to precocious differentiation while decreased signaling leads to delays in differentiation. Importantly, cell fates are unchanged, but tissue organization is lost upon loss of developmental timing controls. These data suggest that intricate developmental decisions are coordinated with nutritional status and tissue growth by the InR signaling pathway.

Animals↗

At the nexus between pattern formation and cell-type specification: the generation of individual neuroblast fates in the Drosophila embryonic central nervous system.

The specification of specific and often unique fates to individual cells as a function of their position within a developing organism is a fundamental process during the development of multicellular organisms. The development of the Drosophila embryonic central nervous system serves as an excellent model system in which to clarify the developmental mechanisms that link pattern formation to cell-type specification. The Drosophila embryonic central nervous system develops from a set of neural stem cells termed neuroblasts. Neuroblasts arise from the ectoderm in an invariant pattern, and each neuroblast acquires a unique fate based on its position within this pattern. Two groups of genes recently have been demonstrated to govern the individual fate specification of neuroblasts. One group, the segment polarity genes, enables neuroblasts that develop in different anteroposterior positions to acquire different fates. The second group, referred to as the columnar genes, ensures that neuroblasts that develop in different dorsoventral domains assume different fates. When integrated, the activities of the segment polarity and columnar genes create a Cartesian coordinate system that bestows unique fates to individual neuroblasts as a function of their position of formation within the ectoderm. BioEssays 1999;21:922-931.

Animals↗

Lipid modifications of proteins - slipping in and out of membranes.

Protein lipid modification, once thought to act as a stable membrane anchor for soluble proteins, is now attracting more widespread attention for its emerging role in diverse signaling pathways and regulatory mechanisms. Most multicellular organisms have recruited specific types of lipids and a suite of unique enzymes to catalyze the modification of a select number of proteins, many of which are evolutionarily conserved in plants, animals and fungi. Each of the three known types of lipid modification - palmitoylation, myristylation and prenylation - allows cells to target proteins to the plasma membrane, as well as to other subcellular compartments. Among the lipid modifications, protein prenylation might also function as a relay between cytoplasmic isoprene biosynthesis and regulatory pathways that control cell cycle and growth. Molecular and genetic studies of an Arabidopsis mutant that lacks farnesyl transferase suggest that the enzyme has a role in abscisic acid signaling during seed germination and in the stomata. It is becoming clear that lipid modifications are not just fat for the protein, but part of a highly conserved intricate network that plays a role in coordinating complex cellular functions.

Journal Article↗

The structure of Escherichia coli cytosine deaminase.

Cytosine deaminase (CD) catalyzes the deamination of cytosine, producing uracil. This enzyme is present in prokaryotes and fungi (but not multicellular eukaryotes) and is an important member of the pyrimidine salvage pathway in those organisms. The same enzyme also catalyzes the conversion of 5-fluorocytosine to 5-fluorouracil; this activity allows the formation of a cytotoxic chemotherapeutic agent from a non-cytotoxic precursor. The enzyme is of widespread interest both for antimicrobial drug design and for gene therapy applications against tumors. The structure of Escherichia coli CD has been determined in the presence and absence of a bound mechanism-based inhibitor. The enzyme forms an (alphabeta)(8) barrel structure with structural similarity to adenosine deaminase, a relationship that is undetectable at the sequence level, and no similarity to bacterial cytidine deaminase. The enzyme is packed into a hexameric assembly stabilized by a unique domain-swapping interaction between enzyme subunits. The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent.

Adenosine Deaminase↗

Influence of microenvironment on mammary epithelial cell survival in primary culture.

Mammary epithelial cells cultured on Engelbreth-Holm-Swarm (EHS) matrix form multicellular structures termed mammospheres, in which cells and matrix become arranged around a central luminal space. In the presence of lactogenic hormones, cells within mammospheres become polarized, form tight intercellular junctions, and secrete milk proteins vectorially into the luminal space. This study examined the mechanism of lumen formation. Histological examination of developing mammospheres showed that cavitation was associated spatially and temporally with the appearance of fragmented nuclear material in apoptotic bodies, and with the presence of cells positively labeled by terminal deoxynucleotide transferase-mediated deoxyuridine nick end-labeling (TUNEL). Analysis of [(32)P]-deoxynucleotide end-labeled genomic DNA by electrophoresis and autoradiography showed DNA laddering indicative of apoptosis. A transient increase in laddering coincided with both lumen formation and the presence of TUNEL-positive cells. Lumen formation, DNA laddering, and detection of TUNEL-positive cells were all accelerated when matrix composition was altered. They were also impaired coordinately when caspase inhibitor was present during the first two days of culture. Therefore, lumen formation in mammosphere cultures is due to selective apoptosis of centrally located cells. Mammosphere cavitation was accompanied by redistribution of matrix constituents to the mammosphere periphery. Western blotting and Western ligand blotting of culture medium showed that lumen formation was also associated with a transient increase in insulin-like growth factor binding protein-5 (IGFBP5), a factor implicated in mammary apoptosis in vivo. We propose that epithelial cell survival during mammosphere development is induced selectively through stabilization by basement membrane constituents, which may act directly on the epithelial cell or confer protection against autocrine apoptotic factors.

Animals↗

Enhancer-binding proteins with a forkhead-associated domain and the sigma54 regulon in Myxococcus xanthus fruiting body development.

In response to starvation, Myxococcus xanthus initiates a developmental program that results in the formation of spore-filled, multicellular fruiting bodies. Many developmentally regulated genes in M. xanthus are transcribed from sigma(54) promoters, and these genes require enhancer-binding proteins. Here we report the finding of an unusual group of 12 genes encoding sigma(54)-dependent enhancer-binding proteins containing a forkhead-associated (FHA) domain as their N-terminal sensory domain. FHA domains in other proteins recognize phosphothreonine residues. An insertion mutation in one of these genes, Mx4885, caused a cell autonomous aggregation and sporulation defect. In-frame deletion mutants showed that the FHA domain is necessary for proper Mx4885 function. The altered pattern of developmental gene expression in the mutant implied that Mx4885 is on the pathway of response to the morphogenetic C-signal. Immunoblots specific for C-signal and FruA imply that the site of Mx4885 action is downstream of FruA synthesis on the C-signal transduction pathway. Mx4885 may help to coordinate the level of intracellular phosphorylated FruA (FruA-P) with the level of C-signal displayed on the signal donor cell. Because FHA domains respond to phosphothreonine-containing proteins, these results suggest a regulatory link to the abundant Ser/Thr protein kinases in M. xanthus.

Amino Acid Sequence↗

Structure of apo-phosphatidylinositol transfer protein alpha provides insight into membrane association.

Phosphatidylinositol transfer protein alpha (PITP alpha) is a ubiquitous and highly conserved protein in multicellular eukaryotes that catalyzes the exchange of phospholipids between membranes in vitro and participates in cellular phospholipid metabolism, signal transduction and vesicular trafficking in vivo. Here we report the three-dimensional crystal structure of a phospholipid-free mouse PITP alpha at 2.0 A resolution. The structure reveals an open conformation characterized by a channel running through the protein. The channel is created by opening the phospholipid-binding cavity on one side by displacement of the C-terminal region and a hydrophobic lipid exchange loop, and on the other side by flattening of the central beta-sheet. The relaxed conformation is stabilized at the proposed membrane association site by hydrophobic interactions with a crystallographically related molecule, creating an intimate dimer. The observed open conformer is consistent with a membrane-bound state of PITP and suggests a mechanism for membrane anchoring and the presentation of phosphatidylinositol to kinases and phospholipases after its extraction from the membrane. Coordinates have been deposited in the Protein Data Bank (accession No. 1KCM).

Animals↗

A case for strain-induced fluid flow as a regulator of BMU-coupling and osteonal alignment.

Throughout life, human bone is renewed continuously in a tightly controlled sequence of resorption and formation. This process of bone remodeling is remarkable because it involves cells from different lineages, collaborating in so-called basic multicellular units (BMUs) within small spatial and temporal boundaries. Moreover, the newly formed (secondary) osteons are aligned to the dominant load direction and have a density related to its magnitude, thus creating a globally optimized mechanical structure. Although the existence of BMUs is amply described, the cellular mechanisms driving bone remodeling-particularly the alignment process-are poorly understood. In this study we present a theory that explains bone remodelling as a self-organizing process of mechanical adaptation. Osteocytes thereby act as sensors of strain-induced fluid flow. Physiological loading produces stasis of extracellular fluid in front of the cutting cone of a tunneling osteon, which will lead to osteocytic disuse and (continued) attraction of osteoclasts. However, around the resting zone and the closing cone, enhanced extracellular fluid flow occurs, which will activate osteocytes to recruit osteoblasts. Thus, cellular activity at a bone remodeling site is well related to local fluid flow patterns, which may explain the coordinated progression of a BMU.

Bone Remodeling↗

Self-assembly of sensory neurons into ganglia-like microtissues.

Unraveling intra- and inter-cellular signaling networks managing cell-fate control, coordinating complex differentiation regulatory circuits and shaping tissues and organs in living systems remain major challenges in the post-genomic era. Resting on the laurels of past-century monolayer culture technologies, the cell culture community has only recently begun to appreciate the potential of three-dimensional mammalian cell culture systems to reveal the full scope of mechanisms orchestrating the tissue-like cell quorum in space and time. Capitalizing on gravity-enforced self-assembly of monodispersed primary embryonic mouse cells in hanging drops, we designed and characterized a three-dimensional cell culture model for ganglion-like structures. Within 24h, a mixture of mouse embryonic fibroblasts (MEF) and cells, derived from the dorsal root ganglion (DRG) (sensory neurons and Schwann cells) grown in hanging drops, assembled to coherent spherical microtissues characterized by a MEF feeder core and a peripheral layer of DRG-derived cells. In a time-dependent manner, sensory neurons formed a polar ganglion-like cap structure, which coordinated guided axonal outgrowth and innervation of the distal pole of the MEF feeder spheroid. Schwann cells, present in embryonic DRG isolates, tended to align along axonal structures and myelinate them in an in vivo-like manner. Whenever cultivation exceeded 10 days, DRG:MEF-based microtissues disintegrated due to an as yet unknown mechanism. Using a transgenic MEF feeder spheroid, engineered for gaseous acetaldehyde-inducible interferon-beta (ifn-beta) production by cotransduction of retro-/ lenti-viral particles, a short 6-h ifn-beta induction was sufficient to rescue the integrity of DRG:MEF spheroids and enable long-term cultivation of these microtissues. In hanging drops, such microtissues fused to higher-order macrotissue-like structures, which may pave the way for sophisticated bottom-up tissue engineering strategies. DRG:MEF-based artificial micro- and macrotissue design demonstrated accurate key morphological aspects of ganglions and exemplified the potential of self-assembled scaffold-free multicellular micro-/macrotissues to provide new insight into organogenesis.

Animals↗

Coordinate regulation of drug metabolism by xenobiotic nuclear receptors: UGTs acting together with CYPs and glucuronide transporters.

Xenobiotic nuclear receptors (PXR, CAR, and the Ah receptor) coordinately induce genes involved in all phases of xenobiotic metabolism including oxidative metabolism, conjugation, and transport. The comment--dedicated to honor the memory of Herbert Remmer, mentor of the author K. W. B.--discusses mechanistic, functional, and evolutionary aspects of xenobiotic nuclear receptors which induce UGTs together with CYPs and glucuronide transporters in human and rodent liver and intestine. Recent findings on regulation of CYPs, UGTs, and transporters suggest that while nuclear receptor signaling induces different CYPs, regulation may converge on single UGTs and transporters. Functional consequences of co-regulation are discussed using examples from the metabolism of xeno- and endobiotics (drugs, bilirubin, bile salts, steroid hormones, and carcinogens). Animal-plant interactions may have been a major driving force in the evolutionary divergence of CYPs and UGTs in mammals and insects as well as in their regulation by nuclear receptors. In addition, regulation by nuclear receptors was probably shaped by the need for homeostatic control of endobiotic signals in the evolution of multicellular organisms.

Animals↗

Switch in gap junction protein expression is associated with selective changes in junctional permeability during keratinocyte differentiation.

Gap junctional communication provides a mechanism for regulating multicellular activities by allowing the exchange of small diffusible molecules between neighboring cells. The diversity of gap junction proteins may exist to form channels that have different permeability properties. We report here that induction of terminal differentiation in mouse primary keratinocytes by calcium results in a specific switch in gap junction protein expression. Expression of alpha 1 (connexin 43) and beta 2 (connexin 26) gap junction proteins is down-modulated, whereas that of beta 3 (connexin 31) and beta 4 (connexin 31.1) proteins is induced. Although both proliferating and differentiating keratinocytes are electrically coupled, there are significant changes in the permeability properties of the junctions to small molecules. In parallel with the changes in gap junction protein expression during differentiation, the intercellular transfer of the small dyes neurobiotin, carboxyfluorescein, and Lucifer yellow is significantly reduced, whereas that of small metabolites, such as nucleotides and amino acids, proceeds unimpeded. Thus, a switch in gap junction protein expression in differentiating keratinocytes is accompanied by selective changes in junctional permeability that may play an important role in the coordinate control of the differentiation process.

Animals↗

The deprivation syndrome is the driving force of phylogeny, ontogeny and oncogeny.

Energy is the motor of life. Energy ensures the organism's survival and competitive advantage for reproductive success. For almost 3 billion years, unicellular organisms were the only life form on earth. Competition for limited energy resources and raw materials exerted an incessant selective pressure on organisms. In the adverse environment and due to their 'feast and famine' life style, hardiness to a variety of stressors, particularly to nutrient deprivation, was the selection principle. Both resistance and mutagenic adaptation to stressors were established as survival strategies by means of context-specific processes creating stability or variability of DNA sequence. The conservation of transduction pathways and functional homology of effector molecules clearly bear witness that the principles of life established during prokaryotic and eukaryotic unicellular evolution, although later diversified, have been unshakably cast to persist during metazoan phylogenesis. A wealth of evidence suggests that unicellular organisms evolved the phenomena of differentiation and apoptosis, sexual reproduction, and even aging, as responses to environmental challenges. These evolutionary accomplishments were elaborated from the dichotomous resistance/mutagenesis response and sophisticated the capacity of cells to tune their genetic information to changing environmental conditions. Notably, the social deprivation responses, differentiation and apoptosis, evolved as intercellularly coordinated events: a multitude of differentiation processes were elaborated from sporulation, the prototypic stress resistance response, while apoptosis, contrary to current concepts, is no altruistic cell suicide but was programmed as a mutagenic survival response; this response, however, is socially thwarted leading into mutagenic error catastrophe. In the hybrid differentiation-apoptosis process, cytocide and cannibalism of apoptotic cells thus serve the purpose of fueling the survival of the selfish genes in the differentiating cells. However, successful mutagenesis, although repressed, persisted in the asocial stress response of carcinogenesis as a regression to primitive unicellular behavior following failure of intercellular communication. While somatic mutagenesis was largely prevented, Metazoa elaborated germ cell mutagenesis as an evolutionary vehicle. Genetic competence, a primitive, stress-induced mating behavior, evolved into sexual reproduction which harnessed mutagenesis by subjecting highly mutable germ cells to a rigid viability selection. These processes were programmatically fixed as life- and cell-cycle events but retained their deprivation response phenotypes. Thus, the differentiation-apoptosis tandem evolved as the 'clay' to mold the specialized structures and functions of a multicellular organism while sexual reproduction elaborated the principle of quality-checked mutagenesis to create the immense diversity of Metazoa following the Cambrian explosion. Throughout these events, reactive oxygen and nitrogen species, which are regulated by energy homeostasis, shape the genetic information in a regulated but random, uncoded process providing the fitness-related feedback of phenotype to genotype. The interplay of genes and environment establishes a dynamic stimulus-response feedback cycle which, in animate nature, may be the organizing principle to contrive the reciprocal duality of energy and matter.

Aging↗

Carbohydrate-carbohydrate interaction as a major force initiating cell-cell recognition.

Sponges were the earliest multicellular organisms to evolve through the development of cell recognition and adhesion processes mediated by cell surface proteoglycans. Information on sponges has an extra added value because, as a group, they are the oldest Metazoans alive and contribute more to our understanding of life on earth than knowledge of other animal groups. Although the proteoglycans are emerging as key players in various physiological and pathophysiological cellular events, little is known about the carbohydrate moiety of the proteoglycan molecule. Until recently there was no evidence provided for the existence of specific and biologically significant carbohydrate-carbohydrate interaction. We show here that the interaction between single oligosaccharides of surface proteoglycans is relatively strong (in the 200-300 piconewtons range) and in the same range as other relevant biological interactions, like those between antibodies and antigens. This carbohydrate-carbohydrate recognition is highly species-specific and perfectly mimics specific cell-cell recognition. Both the strength and the species-specificity of the carbohydrate-carbohydrate interaction are guaranteed by polyvalency, by compositional and architectural differences between carbohydrates, and by the arrangement of the carbohydrate chain in a three-dimensional context. Ca(2+)-ions are essential and probably provide coordinating forces. Our findings confirm the existence and character of species-specific carbohydrate-carbohydrate recognition fundamental to cell recognition and adhesion events.

Animals↗

Symmetry-breaking in mammalian cell cohort migration during tissue pattern formation: role of random-walk persistence.

Coordinated, cohort cell migration plays an important role in the morphogenesis of tissue patterns in metazoa. However, individual cells intrinsically move in a random walk-like fashion when studied in vitro. Hence, in the absence of an external orchestrating influence or template, the emergence of cohort cell migration must involve a symmetry-breaking event. To study this process, we used a novel experimental system in which multiple capillary endothelial cells exhibit spontaneous and robust cohort migration in the absence of chemical gradients when cultured on micrometer-scale extracellular matrix islands fabricated using microcontact printing. A computational model suggested that directional persistence of random-walk and dynamic mechanical coupling of adjacent cells are the critical control parameters for this symmetry-breaking behavior that is induced in spatially-constrained cell ensembles. The model predicted our finding that fibroblasts, which exhibit a much shorter motility persistence time than endothelial cells, failed to undergo symmetry breaking or produce cohort migration on the matrix islands. These findings suggest that cells have intrinsic motility characteristics that are tuned to match their role in tissue patterning. Our results underscore the importance of studying cell motility in the context of cell populations, and the need to address emergent features in multicellular organisms that arise not only from cell-cell and cell-matrix interactions, but also from properties that are intrinsic to individual cells.

Animals↗

Transcription elongation factor SII.

RNA chain elongation by RNA polymerase II (pol II) is a complex and regulated process which is coordinated with capping, splicing, and polyadenylation of the primary transcript. Numerous elongation factors that enable pol II to transcribe faster and/or more efficiently have been purified. SII is one such factor. It helps pol II bypass specific blocks to elongation that are encountered during transcript elongation. SII was first identified biochemically on the basis of its ability to enable pol II to synthesize long transcripts. ((1)) Both the high resolution structure of SII and the details of its novel mechanism of action have been refined through mutagenesis and sophisticated in vitro assays. SII engages transcribing pol II and assists it in bypassing blocks to elongation by stimulating a cryptic, nascent RNA cleavage activity intrinsic to RNA polymerase. The nuclease activity can also result in removal of misincorporated bases from RNA. Molecular genetic experiments in yeast suggest that SII is generally involved in mRNA synthesis in vivo and that it is one type of a growing collection of elongation factors that regulate pol II. In vertebrates, a family of related SII genes has been identified; some of its members are expressed in a tissue-specific manner. The principal challenge now is to understand the isoform-specific functional differences and the biology of regulation exerted by the SII family of proteins on target genes, particularly in multicellular organisms.

Animals↗

Impaired wound contraction in stromelysin-1-deficient mice.

OBJECTIVE: To determine whether the deletion of stromelysin-1, a single metalloproteinase gene product, will alter the time course and quality of dermal wound repair in mice. SUMMARY BACKGROUND DATA: After dermal injury, a highly coordinated program of events is initiated by formation of a fibrin clot, followed by migration of keratinocytes, contraction of the dermis, recruitment of inflammatory macrophages, formation of granulation tissue with angiogenesis, and finally tissue remodeling. Matrix metalloproteinases are rapidly induced in the dermis and granulation tissue and at the leading edge of the epidermis in the healing wounds. METHODS: Incisional and circular full-thickness wounds 2 to 10 mm were made in the dermis of stromelysin-1-deficient and wild-type mice. The wounds were analyzed for rate of cellular migration and epithelialization. The wound contraction was examined by immunohistochemical staining for alpha-smooth muscle actin and fluorescent staining for fibrillar actin. RESULTS: Independent of the age of the animal, excisional wounds in stromelysin-1-deficient mice failed to contract and healed more slowly than those in wild-type mice. Cellular migration and epithelialization were unaffected in the stromelysin-1-deficient animals. The functional defect in these mice is failure of contraction during the first phase of healing because of inadequate organization of actin-rich stromal fibroblasts. CONCLUSIONS: Excisional dermal wound healing is impaired in mice with a targeted deletion in the stromelysin-1 gene. Incisional wound healing is not affected. These data implicate stromelysin-1 proteolysis during early wound contraction and indicate that stromelysin-1 is crucial for the organization of a multicellular actin network.

Animals↗

Characterization of gliding motility in Flexibacter polymorphus.

Motility of the marine gliding bacterium Flexibacter polymorphus was studied by using microcinematographic techniques. Following adhesion to a glass surface, multicellular filaments and individual cells usually began to glide within a few seconds at a speed of approximately 12 micron per second (at 23 degrees C). Adhesion to the glass surface was evidently mediated by multitudes of extremely fine extracellular fibrils. Gliding velocity was independent of filament length but directly related to electron-transport activity and substratum temperature in the range 3-35 degrees C. The rate of gliding was inversely related to medium viscosity, suggesting that the locomotor apparatus functions at constant torque. Forward motion was occasionally interrupted by direction reversals, somersaults (observed primarily in single cells of short filaments), or spinning of filaments tethered by one pole. The frequency of direction reversal was found to be an inverse function of filament length. Translational motility was invariably accompanied by sinistral revolution about the longitudinal axis of a filament. The sense and pitch of revolution were constant among filaments of different length. Polystyrene microspheres or India ink particles adsorbed to gliding cells were actively displaced in either direction, their movement tracing either a regular zigzag or helical path along the filament surface. Because microspheres were also observed to move on nonmotile filaments, particle translocation was evidently not obligatorily linked to gliding locomotion. Multiple particles adsorbed to a single filament often moved independently. The data are consistent with a motility mechanism involving limited motion in numerous mechanically independent (yet functionally coordinated) domains on the cell surface.

Animals↗

[Different regulation systems of cell cycle events (dysregulation of these events in the tumoral cell)].

Preservation of the shape and the integrity of multicellular eukaryotes needs rigorous cell proliferation monitoring. During the prereplicative G1 phase, a finely adjusted and specific control supervises the proliferant/non proliferant states of the cells. Some molecular mechanisms of growth regulation have been identified in recent years. Changes in normal cell attachment on extracellular matrix and intercellular chemical signalling (secretion of informative molecules) activate intracellular signals for division. The transduction mechanisms of the extracellular signalling to the nucleus have been partially elucidated for steroid hormones and growth factors. Molecular biology research and proto-oncogene discoveries have led to considerable progress in understanding the role of these normal genes in the control of cellular proliferation. The initiation of the response to extracellular factors requires: i), direct transducers (specific binding of the steroid hormone on its cytoplasmic or nuclear receptor and high affinity binding of this activated complex to specific DNA sequences); and ii) indirect transducers (binding of growth factors on extracellular domains of specific receptor proteins which convert this extracellular event into several intracellular signals, secondary messengers, protein kinases and specific nuclear regulatory factors). Whatever the transduction system, nuclear events control transcription of growth regulatory genes. The series of enzymatic reactions set in motion by indirect transduction systems require strict regulation systems, the diversity and the complexity of which has been perceived in studies on jun and fos gene families. Each proliferation step is governed by growth stimulators and growth inhibitors, the transformation of normal cells to cancer cells resulting from alterations of these regulatory process. Independent of extracellular stimuli and of their transfer to the nucleus, intracellular controls coordinate cell cycle phases (G1, S, G2 and M) to produce daughter cells identical to the original cell. Two control points are particularly critical: one in G1 (the "start" point) and the other in G2 just before mitosis. Although intermediate steps between extracellular and intracellular controls are still unknown, yeast gene analyses have allowed determination of molecular regulatory mechanisms implicated in the passage of these critical points. A considerable advance was made by the discovery that some of the involved components presented strong sequence and function homologies in organisms from yeast to man, suggesting a phyllogenetically conserved mechanism. It seems likely that the phosphorylation state of protein p34, its association with a G1-phase specific cyclin or a M-phase specific cyclin, and its protein kinase activity regulate the proliferation state of higher eukaryotic cells. In spite of significant advances, much research is still necessary to elucidate all the mechanisms involved in cell cycle control.

CDC2 Protein Kinase↗