Chapter 1 - The Cell As A Unit Of Health And Disease Flashcards
Major classes of functional non-coding sequences of DNA in the human genome
- Promoters and enhancers : provide binding sites for transcription factors
- Binding sites for factors that organize and maintain higher order chromatin structures.
- Non-coding regulatory RNAs: microRNAs and long non-coding RNAs can regulate gene expression
- Mobile genetic elements (transponons): can move around the genome, regulate gene expression, chromatin organization
- Structural regions of DNA: telomeres, centimetres
The organization of nuclear DNA. At the light microscopic level, the nuclear genetic material is organized into dispersed, transcriptionally active euchromatin or densely packed, transcriptionally inactive heterochromatin; chromatin can also be mechanically connected with the nuclear membrane, and nuclear membrane perturbation can thus influence transcription. Chromosomes (as shown) can only be visualized by light microscopy during cell division. During mitosis, they are organized into paired chromatids connected at centromeres; the centromeres act as the locus for the formation of a kinetochore protein complex that regulates chromosome segregation at metaphase. The telomeres are repetitive nucleotide sequences that cap the termini of chromatids and permit repeated chromosomal replication without loss of DNA at the chromosome ends. The chromatids are organized into short “P” (“petite”) and long “Q” (“next letter in the alphabet”) arms. The characteristic banding pattern of chromatids has been attributed to relative GC content (less GC content in bands relative to interbands), with genes tending to localize to interband regions. Individual chromatin fibers are comprised of a string of nucleosomes—DNA wound around octameric histone cores—with the nucleosomes connected via DNA linkers. Promoters are noncoding regions of DNA that initiate gene transcription; they are on the same strand and upstream of their associated gene. Enhancers are regulatory elements that can modulate gene expression over distances of 100 kB or more by looping back onto promoters and recruiting additional factors that are needed to drive the expression of pre-mRNA species. The intronic sequences are subsequently spliced out of the pre-mRNA to produce the definitive message that is translated into protein—without the 3′- and 5′-untranslated regions (UTR). In addition to the enhancer, promoter, and UTR sequences, noncoding elements are found throughout the genome; these include short repeats, regulatory factor binding regions, noncoding regulatory RNAs, and transposons.
The two most common forms of DNA variation in the normal human genome
- Single-nucleotide polymorphisms (SNPs) - variants at single nucleotide position and are almost always biallelic.
- Copy number variation (CNV) - large contiguous stretches of DNA from 1000 to millions of base pairs, may be biallelic or duplications or deletions
DNA-histone complex
147 base pair nucleosome wrapped around a central core of highly conserved low-molecular weight proteins. These complexes connect via short DNA linkers to make up chromatin
Euchromatin vs. Heterochromatin
Euchromatin: cytochemically dispersed and transcriptionally active
Heterochromatin: cytochemically dense and transcriptionally inactive
Histone organization.
A, Nucleosomes are comprised of octamers of histone proteins (two each of histone subunits H2A, H2B, H3, and H4) encircled by 1.8 loops of 147 base pairs of DNA; histone H1 sits on the 20-80 nucleotide linker DNA between nucleosomes and helps stabilizes the overall chromatin architecture. The histone subunits are positively charged, thus allowing the compaction of the negatively charged DNA.
B, The relative state of DNA unwinding (and thus access for transcription factors) is regulated by histone modification, for example, by acetylation, methylation, and/or phosphorylation (so-called “marks”); marks are dynamically written and erased. Certain marks such as histone acetylation “open up” the chromatin structure, whereas others, such as methylation of particular histone residues, tends to condense the DNA and leads to gene silencing. DNA itself can also be also be methylated, a modification that is associated with transcriptional inactivation.
“Chromatin writer complexes” carry out histone modifications (a.k.a marks). What are five categories of marks?
- Histone methylation: lysine or arginine residues get marked, leading to an increase or a decrease in transcription
- Histone acetylation: lysine residues get marked by histone acetyltransferases (HAT). These tend to open up chromatin for transcription (I.e. Euchromatin)
- Histone phosphorylation: either opens up or condenses chromatin for varied effects on transcription
- DNA methylation: high levels at gene regulatory elements. These usually downregulate transcription.
- Chromatin organizing factors: bind to non-coding regions and little is known
Unlike genetic changes, epigenetic changes can be reversible. Provide 2 examples.
- Histone acetylation can be reversed by histone deacetylases (HDACs)
- DNA methylation
2 major categories of non-coding RNA
- miRNAs: mainly modulate translation of target mRNAs post-transcriptionally. Transcription of miRNA -> primary miRNA -> processed by DICER to produce ss miRNAs -> these associate with RISC complex -> if perfect match, cleavage of ss miRNA leads to gene silencing. If imperfect match, translational repression leads to gene silencing
- Long non-coding RNA (lnRNA): modulate gene expression in many ways (gene activation, genr suppression, promotion of chromatin modification, assembly of protein complexes)
Generation of microRNAs (miRNA) and their mode of action in regulating gene function. miRNA genes are transcribed to produce a primary miRNA (pri-miRNA), which is processed within the nucleus to form pre-miRNA composed of a single RNA strand with secondary hairpin loop structures that form stretches of double-stranded RNA. After this pre-miRNA is exported out of the nucleus via specific transporter proteins, the cytoplasmic Dicer enzyme trims the pre-miRNA to generate mature double-stranded miRNAs of 21 to 30 nucleotides. The miRNA subsequently unwinds, and the resulting single strands are incorporated into the multiprotein RNA-induced silencing complex (RISC). Base pairing between the single-stranded miRNA and its target mRNA directs RISC to either cleave the mRNA target or repress its translation. In either case, the target mRNA gene is silenced posttranscriptionally.
Roles of long noncoding RNAs
A: Long non-coding RNAs (lncRNAs) can facilitate transcription factor binding and thus promote gene activation.
B: Conversely, lncRNAs can preemptively bind transcription factors and thus prevent gene transcription.
C: Histone and DNA modification by acetylases or methylases (or deacetylases and demethylases) may be directed by the binding of lncRNAs.
D: In other instances, lncRNAs may act as scaffolding to stabilize secondary or tertiary structures and/or multi-subunit complexes that influence general chromatin architecture or gene activity.
Basic subcellular constituents of cells. The table presents the number of the various organelles within a typical hepatocyte, as well as their volume within the cell. The figure shows geographic relationships but is not intended to be accurate to scale.
Where are proteins destined for the cell membrane or beyond synthesized?
What about proteins intended for the cytosol?
Rough ER ribosomes –> cell membrane or beyond
Free ribosomes –> cytosol
Lysosomes vs. proteasomes vs. peroxisomes – What do they degrade?
Lysosomes: wide array of macromolecules (proteins, polysaccharides, lipids, nucleic acids)
Proteasomes: denatured proteins
Peroxisomes: breakdown of fatty acids - generate H2O2
Plasma membranes are fluid bilayers of amphipathic phospholipids with hydrophobic tails and hydrophilic heads. What are 3 types of likelihood and what should I know about them?
- Phosphatidylinositol: on the inner membrane, electric scaffold for intracellular proteins. Phosphoinositides can be hydrolyzed by phospholipase C to generate diacylglycerol, inositol trisphosphate
- Phosphatidylserine: normally confers a negative charge to the inner layer of the membrane. When it flips to the outside it is an “eat me” signal to elicit apoptosis. Also provides negatively charged surface required for platelet aggregation
- Glycolipids and sphingomyelin: extracellular face, importsnt in cell-cell and cell-matrix function
Plasma membrane organization and asymmetry. The plasma membrane is a bilayer of phospholipids, cholesterol, and associated proteins. The phospholipid distribution within the membrane is asymmetric due to the activity of flippases; phosphatidylcholine and sphingomyelin are overrepresented in the outer leaflet, and phosphatidylserine (negative charge) and phosphatidylethanolamine are predominantly found on the inner leaflet; glycolipids occur only on the outer face where they contribute to the extracellular glycocalyx. Although the membrane is laterally fluid and the various constituents can diffuse randomly, specific domains—lipid rafts—can also stably develop. Membrane-associated proteins may traverse the membrane (singly or multiply) via α-helical hydrophobic amino acid sequences; depending on the membrane lipid content and the hydrophobicity of protein domains, such proteins may have non-random distributions within the membrane. Proteins on the cytosolic face may associate with membranes through post-translational modifications, e.g., farnesylation, or addition of palmitic acid. Proteins on the extracytoplasmic face may associate with the membrane via glycosyl phosphatidyl inositol linkages. Besides protein-protein interactions within the membrane, membrane proteins can also associate with extracellular and/or intracytoplasmic proteins to generate large, relatively stable complexes (e.g., the focal adhesion complex). Transmembrane proteins can translate mechanical forces (e.g., from the cytoskeleton or extracellular matrix) as well as chemical signals across the membrane. It is worth remembering that a similar organization of lipids and associated proteins also occurs within the various organellar membranes.
Plasma membrane: lipid rafts
Distinct lipid domains on plasma membranes.
Membrane proteins have different solubilities in lipid domains so they accumulate in some locations and are depleted in others. This distribution has effects on cell-cell, cell-matrix, interactions and intracellular signaling pathways
Proteins associated with the lipid bilayer are in one of these four arrangements
- Integral (transmembrane proteins) - most common type - (+) charge in cytosol anchors to (-) phospholipid head
- Proteins synthesized in cytosol and post-translationally attached to prenyl groups or fatty acids that insert into plasma membrane
- Glycosylphosphatidylinositol (GPI) anchors on extracellular face of plasma membrane
- Peripheral membrane proteins may be noncovalently associated with true transmembrane proteins
Movement of small molecules and larger structures across membranes. The lipid bilayer is relatively impermeable to all but the smallest and/or most hydrophobic molecules. Thus, the import or export of charged species requires specific transmembrane transporter proteins; the internalization or externalization of large proteins, complex particles, or even cells requires encircling them with segments of the membrane. Small charged solutes can move across the membrane using either channels or carriers; in general, each molecule requires a unique transporter. Channels are used when concentration gradients can drive the solute movement. Carriers are required when solute is moved against a concentration gradient. Receptor-mediated and fluid-phase uptake of material involves membrane bound vacuoles. Caveolae endocytose extracellular fluid, membrane proteins, and some receptor bound molecules (e.g., folate) in a process driven by caveolin proteins concentrated within lipid rafts (potocytosis). Pinocytosis of extracellular fluid and most surface receptor-ligand pairs involves clathrin-coated pits and vesicles. After internalization, the clathrin dissociates and can be re-used, while the resulting vesicle progressively matures and acidifies. In the early and/or late endosome, ligand can be released from its receptor (e.g., iron released from transferrin bound to the transferrin receptor) with receptor recycling to the cell surface for another round. Alternatively, receptor and ligand within endosomes can be targeted to fuse with lysosomes (e.g., epidermal growth factor bound to its receptor); after complete degradation, the late endosome-lysosome fusion vesicle can regenerate lysosomes. Phagocytosis involves the non-clathrin-mediated membrane invagination of large particles—typically by specialized phagocytes (e.g., macrophages or neutrophils). The resulting phagosomes eventually fuse with lysosomes to facilitate the degradation of the internalized material. Transcytosis involves the transcellular endocytotic transport of solute and/or bound ligand from one face of a cell to another. Exocytosis is the process by which membrane-bound vesicles fuse with the plasma membrane and discharge their contents to the extracellular space.
Plasma membrane: Glycocalyx - description and function
Extracellular face of plasma membrane, studded with carbohydrates (i.e. complex oligosaccharides on glycoproteins, glycolipids, or integral proteoglycans)
Function - chemical/mechanical barrier involved in cell-cell, and cell-matrix interactions
Passive membrane diffusion
Small nonpolar molecules (i.e. O2, CO2) dissolve in lipid bilayers, allowing for rapid diffusion. Hydrophobic molecules (i.e. steroid-based molecules like vitamin D, estradiol), and polar molecules < 75 daltons (i.e. water, ethanol, urea) readily diffuse
Plasma membrane: carriers and channels
Plasma proteins used to transport larger polar molecules across membrane
Channel proteins - hydrophilic pores which permit rapid movement of solute (restricted by size and charge)
Carrier proteins - bind a solute and undergo conformational changes to slowly transfer it across plasma membrane. Solute movement can be passive, following an electrical / concentration gradient, or active (carriers) Na-K ATPase prevents osmotic swelling secondary to buildup of intracellular solutes
Plasma membrane: receptor-mediated and fluid-phase uptake
Endocytosis: uptake of fluids/macromolecules - 2 fundamental mechanisms:
- Caveolae-mediated: noncoated plasma membrane invaginations with GPI-linked molecules, cAMP-binding proteins, SRC-kinases, folate receptors (a.k.a. potocytosis) - may be involved in transmembrane molecule delivery (i.e. folate), but heavily implicated in receptor internalization
- Pinocytosis (receptor-mediated) - clathrin-coated pits invaginate when receptors recognize macromolecules (i.e. LDL, transferrin) and fuse with an endosome
Intracellular protein scaffolding (a.k.a. cytoskeleton) is important for these reasons:
- Maintains a particular shape of the cell
- Maintains polarity
- Organize intracellular organelles
- Movement of cells
Three major classes of cytoskeletal proteins
- Actin microfilaments: 5-9 nm fibrils made up of G-actin (globular protein actin) - the most abundant cytosolic protein in cells. This becomes F-actin when it polymerizes. Actins bind myosin to move
- Intermediate filaments: 10 nm fibrils that do not reorganize, but provide tensile strength and allow cells to bear mechanical stress
- Microtubules: 25 nm fibrils made up of polymerized dimers of alpha and beta tubulin. The (-) end is typically embedded in an MTOC (microtubule organizing center, or centrosome)
Cytoskeletal elements and cell-cell interactions. Interepithelial adhesion involves several different surface protein interactions, including through tight junctions and desmosomes; adhesion to the extracellular matrix involves cellular integrins (and associated proteins) within hemidesmosomes.
Types of intermediate filaments
Lamin A, B, C: Nuclear lamina of all cells
Vimentin: mesenchymal cells
Desmin: muscle cells (scaffold for contraction of actin/myosin)
Neurofilaments: axons of neurons
Cytokeratins: 30 distinct varieties in type 1 (acidic) and type II (basic)
Glial fibrillary acidic proteins: glial cells
Two types of ‘motor proteins’ for which microtubules act as connecting cables
Kinesins - antegrade movement of organelles (-) to (+)
Dyneins - retrograde movement of organelles (+) to (-)
Three basic types of cell junctions
- Occluding (tight) junctions: seals cells together to form a barrier that restricts ion transport. Cell-cell interactions are mediated by claudin, occludin, zonulin, catenin. Helps maintain polarity
- Anchoring junctions (desmosomes): Mechanically attach cells and their cytoskeletons to other cells and the ECM.
- Communicating (gap) junctions: Mediate cell-cell passage of chemical/electrical signals. Connexons are the pores formed by connexin proteins
Different types of adhering junctions (desmosomes)
Cadherins undergo homotypic adhesion to form cell-cell junctions (desmosomes)
Spot desmosomes- small adhesive focus
(Spot desmosome cadherins - desmogleins, desmocollins)
Belt desmosomes- broad bands between cells
(Belt desmosome cadherins - E-cadherins)
Hemidesmosomes- ECM connection
(integrins)
Focal adhesion complexes- large macromolecule complexes that can be at hemidesmosomes, generate intracellular signals secondary to shear stress
Whether proteins are synthesized in RER ribosomes or free ribosomes is dependent on this protein sequence
Signal sequences on the N-termini of nascent proteins –> RER syntesis
__________ retain proteins in ER until modifications (i.e. oligomerization, disulfide bond formation) are complete
Chaperone molecules
If a protein fails to fold properly or oligomerize, it is retained and degraded within the ER
What is the ER stress response?
Excess accumulation of misfolded proteins that exceeds the ER’s capacity to edit/degrade them –> ER stress response
Intracellular catabolism.
A, Lysosomal degradation. In heterophagy (right side), lysosomes fuse with endosomes or phagosomes to facilitate the degradation of their internalized contents (see Fig. 1-7). The end-products may be released into the cytosol for nutrition or discharged into the extracellular space (exocytosis). In autophagy (left side), senescent organelles or denatured proteins are targeted for lysosome-driven degradation by encircling them with a double membrane derived from the endoplasmic reticulum and marked by LC3 proteins (microtubule-associated protein 1A/1B-light chain 3). Cell stressors such as nutrient depletion or certain intracellular infections can also activate the autophagocytic pathway.
B, Proteasome degradation. Cytosolic proteins destined for turnover (e.g., transcription factors or regulatory proteins), senescent proteins, or proteins that have become denatured due to extrinsic mechanical or chemical stresses can be tagged by multiple ubiquitin molecules (through the activity of E1, E2, and E3 ubiquitin ligases). This marks the proteins for degradation by proteasomes, cytosolic multi-subunit complexes that degrade proteins to small peptide fragments. High levels of misfolded proteins within the endoplasmic reticulum (ER) trigger a protective unfolded protein response—engendering a broad reduction in protein synthesis, but specific increases in chaperone proteins that can facilitate protein refolding. If this is inadequate to cope with the levels of misfolded proteins, apoptosis is induced.
Lysosomal enzymes are made in ER lumen then tagged with a _____ residue within the golgi
Mannose 6 Phosphate (M6P)
Then they’re delivered to lysosomes through trans-golgi vesicles that have M6P receptors
Macromolecules destined for catabolism in lysosomes arrive by one of three mechanisms
- Internalized by fluid-phase pinocytosis or receptor-mediated endocytosis –> plasma membrane –> early endosome –> late endosome –> mature to lysosome
- Autophagy - senescent organelles and denatured proteins shuttled to lysosome. Double membrane from ER corralls obsolete organelles and expands to form an autophagosome which fuses with lysosome. This preserves cell viability during nutrient depletion.
- Phagocytosis of microorganisms or large matrix fragments - engulfed to form a phagosome and fuses with lysosome
Proteasomes: Roles and other stuff
Role: Degrading cytosolic prteins including denatured/misfolded proteins
Other stuff: Proteins ot be destroyed are designated with a ubiquitin (76 aa protein) Poly-ubiquinated proteins are unfolded and funneled into a proteasome complex –> digestion into small peptide fragments
A few interesting things about mitochondria
- While their genome is small, they carry out all the DNA replication, transcription, translation
- Machinery is similar to present=day bacteria (N-formylmethionine) - so they are sensitive to antibiotics
- Mitochondrial DNA is virtually all maternally inherited, but mitochondrial disorders can be X-linked, autosomal, or maternally inherited
Roles of the mitochondria. Besides the efficient generation of ATP from carbohydrate and fatty acid substrates, mitochondria have an important role in intermediary metabolism, serving as the source of molecules used to synthesize lipids and proteins, and are also are centrally involved in cell life-and-death decisions.
Receptor-mediated signaling.
A, Categories of signaling receptors, including receptors that utilize a nonreceptor tyrosine kinase; a receptor tyrosine kinase; a nuclear receptor that binds its ligand and can then influence transcription; a seven-transmembrane receptor linked to heterotrimeric G proteins; Notch, which recognizes a ligand on a distinct cell and is cleaved yielding an intracellular fragment that can enter the nucleus and influence transcription of specific target genes; and the Wnt/Frizzled pathway where activation releases intracellular β-catenin from a protein complex that normally drives its constitutive degradation. The released β-catenin can then migrate to the nucleus and act as a transcription factor. Lrp5/Lrp6, low-density-lipoprotein (LDL) receptor related proteins 5 and 6, are highly homologous and act as co-receptors in Wnt/Frizzled signaling.
B, Signaling from a tyrosine kinase-based receptor. Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins couples the receptor to inactive, GDP-bound RAS, allowing the GDP to be displaced in favor of GTP and yielding activated RAS. Activated RAS interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates MAPK (mitogen-activated protein kinase) and activated MAP kinase phosphorylates other cytoplasmic proteins and nuclear transcription factors, generating cellular responses. The phosphorylated tyrosine kinase receptor can also bind other components, such as phosphatidyl 3-kinase (PI3 kinase), which activates other signaling systems. The cascade is turned off when the activated RAS eventually hydrolyzes GTP to GDP converting RAS to its inactive form. Mutations in RAS that lead to delayed GTP hydrolysis can thus lead to augmented proliferative signaling. GDP, Guanosine diphosphate; GTP, guanosine triphosphate; mTOR, mammalian target of rapamycin.
TABLE: Growth factors involved in regeneration and repair
Interactions of extracellular matrix (ECM) and growth factors mediated cell signaling. Cell surface integrins interact with the cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin, α-actinin, and talin; see Fig. 1-16C). This can initiate the production of intracellular messengers or can directly transduce signals to the nucleus. Cell surface receptors for growth factors can activate signal transduction pathways that overlap with those mediated through integrins. Signals from ECM components and growth factors can be integrated by the cells to produce a given response, including changes in proliferation, locomotion, and/or differentiation.
Main components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive glycoproteins. Both epithelial and mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins. Basement membranes and interstitial ECM have different architecture and general composition, although certain components are present in both. For the sake of clarity, many ECM components (e.g., elastin, fibrillin, hyaluronan, and syndecan) are not included.
Extracellular matrix (ECM) components.
A, Fibrillar collagen, and elastic tissue structures. Due to rodlike fibril stacking and extensive lateral cross-linking (through the activity of lysyl oxidase), collagen fibers have marked tensile strength but do not have much elasticity. Elastin is also massively cross-linked through lysyl oxidase activity but differs in having large hydrophobic segments that form a dense globular configuration at rest. As stretch is exerted, the hydrophobic domains are pulled open, but the cross-links keep the tissue intact; release of the stretch tension allows the hydrophobic domains of the proteins to refold.
B, Proteoglycan structure. The highly negatively charged sulfated sugars on the proteoglycan “bristles” recruit sodium and water to generate a viscous, but compressible matrix. C, Regulation of basic fibroblast growth factor (bFGF, FGF-2) activity by ECM and cellular proteoglycans. Heparan sulfate binds bFGF secreted in the ECM. Syndecan is a cell surface proteoglycan with a transmembrane core protein and extracellular glycosaminoglycan side chains that can bind bFGF, with a cytoplasmic tail that interacts with the intracellular actin cytoskeleton. Syndecan side chains bind bFGF released from damaged ECM, thus facilitating a concentrated interaction with cell surface receptors.
Collagen biosynthetic pathway. The α-chains that make up a fibrillar collagen molecule are synthesized as precursor pro-α-chains, with large globular polypeptide regions flanking the central triple-helical domain. After proline and lysine hydroxylation and lysine glycosylation within the endoplasmic reticulum, three procollagen chains align to form a triple helix. For all the fibrillar collagens, the C-propeptide is completely removed by endoproteinase activity after secretion, and the resulting triple-helical rod-like domains polymerize in a staggered fashion into fibrillar arrays. After secretion, the collagen achieves lateral stability though collagen cross-linking involving lysyl oxidase and the previously hydroxylated residues. Defects in primary sequence, procollagen endopeptidase processing, hydroxylation, or cross-linking can all lead to weak connective tissues. The specific tissues affected (e.g., blood vessels, skin, bone, ligaments) by such disorders is based on the type of collagen that predominates in that tissue.
Cell and extracellular matrix (ECM) interactions: adhesive glycoproteins and integrin signaling.
A, Fibronectin consists of a disulfide-linked dimer, with several distinct domains that allow binding to ECM and to integrins, the latter through arginine-glycine-aspartic acid (RGD) motifs.
B, The cross-shaped laminin molecule is one of the major components of basement membranes; its multi-domain structure allows interactions between type IV collagen, other ECM components, and cell-surface receptors.
C, Integrins and integrin-mediated signaling events at focal adhesion complexes. Each α-β heterodimeric integrin receptor is a transmembrane dimer that links ECM and intracellular cytoskeleton. It is also associated with a complex of linking molecules (e.g., vinculin, and talin) that can recruit and activate kinases that ultimately trigger downstream signaling cascades.
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.
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.
