Biología de la Diferenciación Celular

Tema 1. El ciclo celular. Fases y puntos de control.

Mecanismos de regulación del ciclo celular.

La reproducción sexual: meiosis. Concepto,

fases y significado biológico
 El ciclo celular. Fases y regulación

1. La proliferación celular

2. Fases del ciclo celular

Fase G1
Fase S
Fase G2
Fase M

3. Puntos de control (checkpoints) del ciclo celular

4. Mecanismos de regulación del ciclo celular

Ciclinas
Quinasas dependientes de ciclinas (Cdk)
Inhibidores de complejos ciclinas-Cdk (Cdi)

5. La reproducción sexual: meiosis. Concepto, fases y significado biológico

 1. La proliferación celular

Tejidos con división celular constante

Médula ósea (producción de las células sanguíneas)
Epitelios (epidermis, intestino, etc.)
Gónadas (gametogénesis)
Glándulas sebáceas

Tejidos con división celular lenta

Endotelio vascular (división cada tres años)
Piel (dermis y epidermis tras lesión)
Hígado (división una vez/año; se incrementa tras una pérdida parcial de
hepatocitos)

Tejidos sin división celular

Nervioso
Tejido muscular estriado
2. Fases del ciclo celular
ORGANISMOS: Uni- o pluricelulares

Hombre adulto: Trillones de células de 200 tipos distintos

CICLO CELULAR → Ciclo reproductivo de una

célula

• Replicación del material genético (DNA)

• División del núcleo (mitosis)

• División del citoplasma (citoquinesis)

 Fases del ciclo de una célula eucariótica típica

G1
S
G2
M

Figura 17.4. Alberts et al., 2008.

 Ciclo celular en las células embrionarias

Figure 14.2. Embryonic cell cycles Early embryonic cell cycles rapidly divide the cytoplasm of the egg into smaller cells. The
cells do not grow during these cycles, which lack G1 and G2 and consist simply of short S phases alternating with M phases.
(Cooper y Hausman, 2004).
 Determinación del
contenido de DNA
celular

Figure 17-13. Analysis of DNA content with a flow

cytometer. This graph shows typical results obtained for
a proliferating cell population when the DNA content of
its individual cells is determined in a flow cytometer. (A
flow cytometer, also called a fluorescence-activated cell
sorter, or FACS, can also be used to sort cells according
to their fluorescence see Figure 8-2). The cells analyzed
here were stained with a dye that becomes fluorescent
when it binds to DNA, so that the amount of
fluorescence is directly proportional to the amount of
DNA in each cell. The cells fall into three categories:
those that have an unreplicated complement of DNA
and are therefore in G1 phase, those that have a fully
replicated complement of DNA (twice the G1 DNA
content) and are in G2 or M phase, and those that have
an intermediate amount of DNA and are in S phase. The
distribution of cells in the case illustrated indicates that
there are greater numbers of cells in G1 phase than in
G2 + M phase, showing that G1 is longer than G2 + M
in this population. (Alberts et al., 2008).
 Marcaje de células en fase S

Figure 17-11. Labeling S-phase cells. (A) The tissue has been exposed for a short period to 3H-thymidine and the labeled cells have
been visualized by autoradiography. Silver grains (black dots) in the photographic emulsion over a nucleus indicate that the cell
incorporated 3H-thymidine into its DNA and thus was in S phase some time during the labeling period. In this specimen, showing the
sensory epithelium from the inner ear of a chicken, the presence of an S-phase cell is evidence of cell proliferation occurring in response
to damage. (B) An immunofluorescence micrograph of BrdU-labeled glial precursor cells in culture. The cells were exposed to BrdU for
4 h and were then fixed and labeled with fluorescent anti-BrdU antibodies (red). All the cells are stained with a blue fluorescent dye.
(Alberts et al., 2002).
Incorporación de 3H-Timidina a células en cultivo
 Fases del ciclo celular: la interfase

Interfase
G1
S
G2
Mitosis
Figure 14.1. Phases of the cell cycle
The division cycle of most eukaryotic
cells is divided into four discrete phases:
M, G1, S, and G2. M phase (mitosis) is
usually followed by cytokinesis. S phase
is the period during which DNA
replication occurs. The cell grows
throughout interphase, which includes
G1, S, and G2. The relative lengths of
the cell cycle phases shown here are
typical of rapidly replicating mammalian
cells. (Cooper y Hausman, 2004).
Cromosomas aislados en distintas fases
del ciclo celular
 Fases del ciclo celular: la fase G1

Interfase
G1
S
G2
Mitosis
Figure 14.1. Phases of the cell cycle
The division cycle of most eukaryotic
cells is divided into four discrete phases:
M, G1, S, and G2. M phase (mitosis) is
usually followed by cytokinesis. S phase
is the period during which DNA
replication occurs. The cell grows
throughout interphase, which includes
G1, S, and G2. The relative lengths of
the cell cycle phases shown here are
typical of rapidly replicating mammalian
cells. (Cooper y Hausman, 2004).
 Regulación del ciclo celular por factores de
crecimiento. La fase G0

Figure 14.6. Regulation of animal

cell cycles by growth factors The
availability of growth factors
controls the animal cell cycle at a
point in late G1 called the restriction
point. If growth factors are not
available during G1, the cells enter a
quiescent stage of the cycle called
G0. (Cooper y Hausman, 2004).
Algunos factores de crecimiento proteicos y sus
funciones
 Fases del ciclo celular: la fase de síntesis

Interfase
G1
S
G2
Mitosis
Figure 14.1. Phases of the cell cycle
The division cycle of most eukaryotic
cells is divided into four discrete phases:
M, G1, S, and G2. M phase (mitosis) is
usually followed by cytokinesis. S phase
is the period during which DNA
replication occurs. The cell grows
throughout interphase, which includes
G1, S, and G2. The relative lengths of
the cell cycle phases shown here are
typical of rapidly replicating mammalian
cells. (Cooper y Hausman, 2004).
 Marcaje de células en fase S

Anti-bromodeoxiuridina
Intestino de pez cebra

Figure 17-12. Labeling S-phase cells. An immunofluorescence micrograph of BrdU-labeled epithelial cells of the
zebrafish gut. The cells were exposed to BrdU for 4 h and were then fixed and labeled with fluorescent anti-BrdU
antibodies (green). All the cells are stained with a red fluorescent dye. (Alberts et al., 2008).
El cromosoma mitótico

Cromátidas
Centrómero
Cinetócoro
Telómeros

Histonas
11.3-21.0 kDa

Figure 17-26. Scanning electron

micrograph of human mitotic
chromosome. (Alberts et al., 2008).
 Fases del ciclo celular: la fase G2

Interfase
G1
S
G2
Mitosis
Figure 14.1. Phases of the cell cycle
The division cycle of most eukaryotic
cells is divided into four discrete phases:
M, G1, S, and G2. M phase (mitosis) is
usually followed by cytokinesis. S phase
is the period during which DNA
replication occurs. The cell grows
throughout interphase, which includes
G1, S, and G2. The relative lengths of
the cell cycle phases shown here are
typical of rapidly replicating mammalian
cells. (Cooper y Hausman, 2004).
Fases del ciclo celular: la fase M

- Profase
- Prometafase
- Metafase
- Anafase
- Telofase

Figure 14.1. Phases of the cell cycle

The division cycle of most eukaryotic
cells is divided into four discrete phases:
M, G1, S, and G2. M phase (mitosis) is
usually followed by cytokinesis. S phase
is the period during which DNA
replication occurs. The cell grows
throughout interphase, which includes
G1, S, and G2. The relative lengths of
the cell cycle phases shown here are
typical of rapidly replicating mammalian
cells. (Cooper y Hausman, 2004).
 Profase

Prometafase
Interfase

Fases de la
mitosis Metafase

Telofase
Anafase

Figure 14.23. Stages of mitosis in an animal cell During

prophase, the chromosomes condense and centrosomes
Citocinesis move to opposite sides of the nucleus, initiating formation
of the mitotic spindle. Breakdown of the nuclear envelope
then allows spindle microtubules to attach to the
kinetochores of chromosomes. During prometaphase, the
chromosomes shuffle back and forth between the
centrosomes and the center of the cell, eventually aligning
in the center of the spindle (metaphase). At anaphase, the
sister chromatids separate and move to opposite poles of
the spindle. Mitosis then ends with re-formation of nuclear
envelopes and chromosome decondensation during
telophase, and cytokinesis yields two interphase daughter
cells. Note that each daughter cell receives one centrosome,
which duplicates prior to the next mitosis.
Principales estadíos de la fase M (mitosis y citocinesis) en una célula animal

PROPHASE PROMETAPHASE

METAPHASE ANAPHASE
Principales estadíos de la fase M (mitosis y citocinesis) en una célula animal

TELOPHASE CYTOKINESIS

Panel 17-1. Principales estadíos de la fase M (mitosis y citocinesis) en una célula animal.
(Alberts et al., 2008).
 Profase

PROPHASE
At prophase, the replicated chromosomes, each consisting of
two closely associated sister chromatids, condense. Outside the
nucleus, the mitotic spindle assembles between the two
centrosomes, which have replicated and moved apart.
For simplicity, only three chromosomes are shown.
In diploid cells, there would be two copies of each chromosome
present. In the photomicrograph, chromosomes are stained
orange and microtubules are green. (Alberts et al., 2002-2008). t = 0 minutes
 Prometafase

PROMETAPHASE

Prometaphase starts abruptly with the

breakdown of the nuclear envelope.
Chromosomes can now attach to spindle
microtubules via their kinetochores and
undergo active movement. (Alberts et al.,
2002-2008).
t = 79 minutes
El huso mitótico en
células animales

Figure 16-85. The mitotic

spindle in animal cells.
(Alberts et al., 2008).
El cinetocoro

Figure 17-36. The kinetochore. (Alberts et al., 2008).

 Cromosomas en metafase distribuidos en el
huso mitótico

Figure 16-85. Chromosomes at the metaphase plate of a mitotic spindle. In this fluorescence micrograph, kinetochores
are labeled in red, microtubules in green, and chromosomes in blue. (Alberts et al., 2008).
 El centrosoma

Figure 17-29. The centrosome. (A) Electron micrograph of an S-phase mammalian cell in
culture, showing a duplicated centrosome. Each centrosome contains a pair of centrioles;
although the centrioles have duplicated, they remain together in a single complex, as shown in
the drawing of the micrograph in (B). One centriole of each centriole pair has been cut in cross-
section, while the other is cut in longitudinal section, indicating that the two members of each
pair are aligned at right angles to each other. The two halves of the replicated centrosome, each
consisting of a centriole pair surrounded by matrix, will split and migrate apart to initiate the
formation of the two poles of the mitotic spindle when the cell enters M phase. (C) Electron
micrograph of a centriole pair that has been isolated from a cell. The two centrioles have partly
separated during the isolation procedure but remain tethered together by fine fibers, which keep
the centriole pair together until it is time for them to separate. Both centrioles are cut
longitudinally, and it can now be seen that the two have different structures: the mother
centriole is larger and more complex than the daughter centriole, and only the mother centriole
is associated with matrix that nucleates microtubules. Each daughter centriole will mature
during the next cell cycle, when it will replicate to give rise to its own daughter centriole.
(Alberts et al., 2008).
 Metafase

METAPHASE

At metaphase, the chromosomes are aligned

at the equator of the spindle, midway
between the spindle poles. The kinetochore
microtubules attach sister chromatids to
opposite poles of the spindle. (Alberts et al.,
2002-2008).
t = 250 minutes
Cromosomas humanos en metafase
 Anafase

ANAPHASE

At anaphase, the sister chromatids synchronously

separate to form two daughter chromosomes, and each
is pulled slowly toward the spindle pole it faces. The
kinetochore microtubules get shorter, and the spindle
poles also move apart; both processes contribute to
chromosome segregation. (Alberts et al., 2002-2008).
t = 279 minutes
 Anafase
Separación de las cromátidas hermanas

Metafase Anafase
Figure 17-43. Sister chromatide separation at anaphase. (Alberts et al., 2008).
En la transición de metafase (A) a anafase (B), las cromátidas hermanas se separan y dirigen hacia los polos opuestos del huso mitótico
(Haemantus, liliácea).
Microtúbulos asociados al cinetocoro

Figure 17-36. The kinetochore.

(Alberts et al., 2008).
 Telofase

TELOPHASE

During telophase, the two sets of daughter

chromosomes arrive at the poles of the spindle and
decondense. A new nuclear envelope reassembles
around each set, completing the formation of two
nuclei and marking the end of mitosis. The division
of the cytoplasm begins with contraction of the
contractile ring. (Alberts et al., 2002-2008).
t = 315 minutes
 Citocinesis

CYTOKINESIS

During cytokinesis, the cytoplasm is divided in

two by a contractile ring of actin and myosin
filaments, which pinches the cell in two to
create two daughters, each with one nucleus.
(Alberts et al., 2002-2008).
t = 362 minutes
 Citocinesis
Actina

Miosina

Figure 17-50. The contractile ring. (A) A drawing of the cleavage furrow in a dividing cell. (B) An electron micrograph of the
ingrowing edge of a cleavage furrow of a dividing animal cell. (C) Fluorescence micrographs of a dividing slime mold amoeba
stained for actin (red) and myosin II (green). Whereas all of the visible myosin II has redistributed to the contractile ring, only some
of the actin has done so; the rest remains in the cortex of the nascent daughter cells. (Alberts et al., 2008).
 Citocinesis

Figure 17-51. The midbody.

(A) A scanning electron
micrograph of an animal cell in
culture in the process of
dividing; the midbody still joins
the two daughter cells. (B) A
conventional electron
micrograph of the midbody of a
dividing animal cell. Cleavage is
almost complete, but the
daughter cells remain attached
by this thin strand of cytoplasm
containing the remains of the
central spindle. (Alberts et al.,
2008).
Figure 18-8. The course of mitosis in a typical animal cell. (Alberts et al., 2002).
 Mitosis y citocinesis en una célula vegetal

Profase Prometafase Metafase

Anafase Telofase Citocinesis

Figure 18-9. The course of mitosis in a plant cell. These light micrographs of a living Haemanthus (lily) cell were taken at the times indicated, using differential-interference-contrast
microscopy. The cell has unusually large chromosomes that are easy to see. (A) At prophase, the chromosomes condense and are clearly visible in the cell nucleus. (B and C) At
prometaphase, the nuclear envelope breaks down and the chromosomes interact with the microtubules that emanate from the two spindle poles. Plants do not have centrosomes, but their
spindle poles contain proteins related to those found in the centrosomal matrix of animal cells. (D) At metaphase, the chromosomes line up at the equator of the spindle. (E) At anaphase,
the daughter chromosomes separate and start moving to opposite poles. (F) At telophase, the chromosomes decondense and daughter nuclei re-form (not seen). (G and H) During
cytokinesis, a new cell wall (the cell plate, red arrows) forms between the two nuclei (N). (Alberts et al., 2002).
 Citocinesis en una célula vegetal
Figure 17-57. The special features of cytokinesis in a higher plant cell. The division plane is established before M phase by a band of microtubules and actin filaments (the preprophase
band) at the cell cortex. At the beginning of telophase, after the chromosomes have segregated, a new cell wall starts to assemble inside the cell at the equator of the old spindle. The overlap
microtubules of the mitotic spindle remaining at telophase form the phragmoplast and guide vesicles derived from the Golgi apparatus toward the center of the spindle. The vesicles are filled
with cell-wall material and fuse to form the growing new cell wall, which grows outward to reach the plasma membrane and original cell wall at the site determined earlier by the preprophase
band. The plasma membrane and the membrane surrounding the new cell wall fuse, completely separating the two daughter cells. (Alberts et al., 2008).
 CARIOTIPO: Imagen descriptiva
22 pares de autosomas, 1 par sexual

Figure 4-10. Human chromosomes. These chromosomes, from a male, were isolated from a cell undergoing nuclear division (mitosis) and are therefore highly compacted.
Each chromosome has been "painted" a different color to permit its unambiguous identification under the light microscope. Chromosome painting is performed by exposing
the chromosomes to a collection of human DNA molecules that have been coupled to a combination of fluorescent dyes. For example, DNA molecules derived from
chromosome 1 are labeled with one specific dye combination, those from chromosome 2 with another, and so on. Because the labeled DNA can form base pairs, or hybridize,
only to the chromosome from which it was derived, each chromosome is differently labeled. For such experiments, the chromosomes are subjected to treatments that separate
the double-helical DNA into individual strands, designed to permit base-pairing with the single-stranded labeled DNA while keeping the chromosome structure relatively
intact. (A) The chromosomes visualized as they originally spilled from the lysed cell. (B) The same chromosomes artificially lined up in their numerical order. This
arrangement of the full chromosome set is called a karyotype. (Alberts et al., 2008).
Organismo nº de cromosomas (célula haploide)

Levadura 16
Dyctyostelium discoideum 7
Arabidopsis thaliana 5
Caenorhabditis elegans 6
Drosophila melanogaster 4
Xenopus laevis 18
Pez pulmonado 17
Pollo 39
Ratón 20
Vaca 30
Perro 39
Hombre 23
Células somáticas → 2n (cromosomas homólogos)
Gametos → n
3. Puntos de control (checkpoints) del ciclo
celular
Puntos de control
(checkpoints) del
ciclo celular

Figure 17-14. The control of the cell

cycle. Information about the completion
of cell-cycle events, as well as signals
from the environment, can cause the
control system to arrest the cycle at
specific checkpoints. The most
prominent checkpoints occur at
locations marked with yellow boxes.
(Alberts et al., 2008).
4. Regulación del ciclo celular
 Regulación del ciclo celular

Ciclinas

Quinasas dependientes de ciclinas: CDK o cdc

Inhibidores de complejos ciclinas-CDK: CDI o CKI

Componentes fundamentales del sistema de
control del ciclo celular

Figure 17-15. Two key components

of the cell-cycle control system. A
complex of cyclin with Cdk acts as a
protein kinase to trigger specific cell-
cycle events. Without cyclin, Cdk is
inactive. (Alberts et al., 2008).
Componentes del sistema de control del ciclo celular
Ciclinas
Proteínas reguladoras especializadas que controlan el ciclo celular
Se unen a moléculas de Cdk y controlan su capacidad para fosforilar
determinadas proteínas diana
Experimentan un ciclo de síntesis y degradación en cada ciclo celular
Las primeras ciclinas descritas forman parte del factor promotor de la
maduración o factor promotor de la mitosis (MPF)

CDK (Quinasas dependientes de ciclinas) o Cdc (Control del ciclo de división

celular
Proteínas quinasas dependientes de ciclina
Fosforilan proteínas específicas en serina y treonina

Procesos centrales que dirigen el ciclo celular

Ensamblaje cíclico ciclina-Cdk Æ Activación Æ Desensamblaje ciclina-Cdk
El núcleo del sistema de control del ciclo celular

Figure 17-16. A simplified view of

the core of the cell-cycle control
system. Cdk associates successively
with different cyclins to trigger the
different events of the cycle. Cdk
activity is usually terminated by
cyclin degradation. For simplicity,
only the cyclins that act in S phase
(S-cyclin) and M phase (M-cyclin)
are shown, and they interact with a
single Cdk; as indicated, the resulting
cyclin-Cdk complexes are referred to
as S-Cdk and M-Cdk, respectively.
(Alberts et al., 2002).
 Desarrollo embrionario temprano
Ensayo de MPF

Figure 17-15. Assaying for MPF by injection into a Xenopus oocyte. MPF can be detected because it drives the oocyte into M
phase. The large nucleus (or "germinal vesicle") of the oocyte breaks down as the mitotic spindle forms. (Alberts et al., 1993).
Variación en los niveles de ciclinas A y B y MPF
en el ciclo celular

Figura 17.19. Incremento y decremento de los niveles de ciclina y de MPFF

durante el ciclo celular de embriones tempranos. (Alberts et al., 1994).
Degradación de proteínas dependiente de ubicuitina
y del proteasoma

Ubiquitin-dependent protein degradation. (Alberts et al., 1994).

 ATP AMP

E1

E1 Poliubicuitinación

E2

E3

ATP

Poliubicuitinación de AMP

proteínas y degradación por Proteasoma

26S
proteasomas
Péptidos
 Estructura de los proteasomas

19S
PA28

ATP

PA28-proteasoma Proteasoma
20S
Proteasoma
26S
 Tipos de ciclinas
Ciclinas G1/S
Se unen a las Cdk al final de la fase G1
Estimulan la progresión a través de start Æ Entrada en el ciclo celular

Ciclinas S
Se unen a las Cdk durante la fase S
Activan la replicación del DNA fosforilando los complejos de pre-replicación
Contribuyen al control de algunos eventos de la mitosis temprana

Ciclinas M
Se unen a las moléculas de Cdk durante la fase G2
Son necesarias para entrar en mitosis
Ciclina mitótica + Cdk Æ MPF (factor promotor de la mitosis)

Ciclinas G1
Se unen a las moléculas de Cdk durante la fase G1
Ayudan a regular la actividad de las ciclinas G1/S, que controlan la progresión del
ciclo a través de start al final de la fase G1
 Principales complejos ciclina-Cdk

Complejo Ciclina Cdk asociada

Cdk-ciclina

Cdk-G1 Ciclina D Cdk4, Cdk6

Cdk-G1/S Ciclina E Cdk2

Cdk-S Ciclina A Cdk2, Cdk1

Cdk-M Ciclina B Cdk1

 Complejos ciclinas-Cdks

Existen diferentes combinaciones de Cdks-ciclinas que fosforilan diferentes proteínas diana y que
ponen en marcha, por tanto, diferentes pasos del ciclo celular

1. Unión de ciclinas mitóticas a Cdks mitóticas Æ complejo MPF

Desencadena la mitosis al fosforilar a las proteínas que intervienen en los siguientes procesos:
- rotura de la membrana nuclear: fosforilación de laminas
- fosforilación de la histona H1 (empaquetamiento del DNA)
- fosforilación de las proteínas asociadas a microtúbulos (huso mitótico)
- fragmentación del retículo endoplásmico
- fragmentación del complejo de Golgi, etc.

2. Unión de ciclinas de la fase S a Cdks de la fase S Æ activa otro complejo

Cdk-ciclina
Actúa sobre la maquinaria que desencadena la replicación del DNA y, así, la entrada en la fase
S del ciclo celular
 Mecanismos de control del ciclo celular
1. Transcripción de los genes que codifican las ciclinas

2. Proteólisis de las ciclinas y otros reguladores

SCF: Complejo enzimático activo en las fases G1 y S
Ubiquitinización y degradación de las ciclinas G1/S y de ciertas CKI
que controlan el comienzo de la fase S
APC/C: Complejo promotor de la anafase que actúa en la fase M
Ubiquitinización y degradación de las ciclinas M y de otros reguladores
de la mitosis

3. Mecanismos de fosforilación y desfosforilación de Cdk

CAK: Quinasa activadora de Cdk: Activa Cdk por fosforilación

Wee1: Fosforilación por la quinasa Wee1 inhibe la actividad de Cdk

Cdc25: Desfosforilación por la fosfatasa Cdc25 aumenta la actividad de Cdk

4. Unión de proteínas inhibidoras de Cdk (CKI, Cdk inhibitor proteins)

CKI: Participan principalmente en el control de las fases G1 y S
 Mecanismo de activación de Cdks
Fosforilación de Cdk por CAK (quinasa activadora de Cdk)

Figure 17-17. The structural basis of Cdk activation. These drawings are based on three-dimensional structures of human Cdk2, as
determined by x-ray crystallography. The location of the bound ATP is indicated. The enzyme is shown in three states. (A) In the inactive
state, without cyclin bound, the active site is blocked by a region of the protein called the T-loop (red). (B) The binding of cyclin causes
the T-loop to move out of the active site, resulting in partial activation of the Cdk2. (C) Phosphorylation of Cdk2 (by CAK) at a threonine
residue in the T-loop further activates the enzyme by changing the shape of the T-loop, improving the ability of the enzyme to bind its
protein substrates. (Alberts et al., 2008).
 Regulación de la actividad de Cdks
Fosforilación de Cdk por Wee 1 / Desfosforilación de Cdk por Cdc25

Figure 17-18. The regulation of Cdk activity by inhibitory phosphorylation. The active cyclin-Cdk complex is turned off when the
kinase Wee1 phosphorylates two closely spaced sites above the active site. Removal of these phosphates by the phosphatase Cdc25 results
in activation of the cyclin-Cdk complex. For simplicity, only one inhibitory phosphate is shown. The activating phosphate is added by
CAK, as shown in Figure 17-17. (Alberts et al., 2008).
Regulación de la actividad de Cdks por la degradación de
ciclinas en el ciclo celular

Alberts et al., 1994.

Actividad de los complejos Cdk-ciclinas de mamíferos a lo
largo del ciclo celular

Figure 20-32. Activity of mammalian

Cdkcyclin complexes through the course
of the cell cycle in G0 cells induced to
divide by treatment with growth factors.
The width of the colored bands is
approximately proportional to the protein
kinase activity of the indicated complexes.
Cyclin D refers to all three D-type cyclins.
(Lodish et al., 2008).
 Complejo ciclina D-Cdk4

Fosforilación de la proteína RB (retinoblastoma)

Proteína Rb: producto del gen supresor de tumores Rb

Rb hipofosforilada
Unión e inhibición del factor de transcripción E2F
Bloqueo de la progresión del ciclo celular en G1

Rb fosforilada
No es capaz de unirse a E2F
Entrada en la fase S
 Regulación del ciclo celular por Rb y E2F

Figure 14.20. Cell cycle regulation of Rb and E2F In its underphosphorylated form, Rb binds to members of the E2F family,
repressing transcription of E2F-regulated genes. Phosphorylation of Rb by Cdk4, 6/cyclin D complexes results in its dissociation
from E2F in late G1. E2F then stimulates expression of its target genes, which encode proteins required for cell cycle progression.
(Cooper y Hausman, 2004).
 Tipos de CKI

Se conocen dos clases de CKIs que difieren en estructura, mecanismo de inhibición y

especificidad

· Clase I: proteínas p21, p27 y p57

Inhiben preferentemente a las CDKs que actúan en las fases G1 y S

Proteína p21
Inhibidor de los complejos ciclina D-CDK4 y ciclina E- CDK2
Bloquea el ciclo celular en la transición G1-S
Puede unirse a PCNA (Proliferanting Cell Nuclear Antigen)
e inhibir la síntesis de DNA

· Clase II: proteínas p16, p15, p18 y p19

p16 es codificada por el gen supresor de tumores MTS1
p15 es codificada por el gen supresor de tumores MTS2
Forman complejos con la ciclina D o las CDK4 y CDK6
Inducción de p21 tras
daño del DNA

Figure 14.21. Induction of p21 by DNA damage

DNA damage results in the elevation of intracellular
levels of p53, which activates transcription of the gene
encoding the Cdk inhibitor p21. In addition to
inhibiting cell cycle progression by binding to
Cdk/cyclin complexes, p21 may directly inhibit DNA
synthesis by interacting with PCNA (a subunit of DNA
polymerase d). (Cooper y Hausman, 2004).

PCNA (Proliferanting Cell Nuclear Antigen)

 CKI: Inhibición del complejo ciclina-Cdk

Figure 17-19. The inhibition of a cyclin-Cdk complex by a CKI. This drawing is based on the three-dimensional structure of the human cyclin
A -Cdk2 complex bound to the CKI p27, as determined by x-ray crystallography. The p27 binds to both the cyclin and Cdk in the complex,
distorting the active site of the Cdk. It also inserts into the ATP-binding site, further inhibiting the enzyme activity. (Alberts et al., 2008).
 Control de la proteolisis por SCF en el ciclo celular

Figure 17-20. The control of proteolysis by SCF and APC during the cell cycle. The phosphorylation of a target protein, such as the
CKI shown, allows the protein to be recognized by SCF, which is constitutively active. With the help of two additional proteins called E1
and E2, SCF serves as a ubiquitin ligase that transfers multiple ubiquitin molecules onto the CKI protein. The ubiquitylated CKI protein is
then immediately recognized and degraded in a proteasome. (Alberts et al., 2008).
 Control de la proteólisis por APC/C en el ciclo celular
APC: complejo promotor de la anafase

Figure 17-20. The control of proteolysis by SCF and APC during the cell cycle. M-cyclin ubiquitylation is performed by
APC, which is activated in late mitosis by the addition of an activating subunit to the complex. Both SCF and APC contain
binding sites that recognize specific amino acid sequences of the target protein. (Alberts et al., 2008).
 Principales proteínas reguladoras del ciclo celular
Proteínas quinasas y fosfatasas que modifican Cdk
Quinasa activadora de Cdk (CAK) Fosforila un sitio activador de las Cdk
Quinasa Wee1 Fosforila sitios inhibidores de las Cdk; controla la entrada en M
Fosfatasa Cdc25 (A, B, C) Elimina fosfatos inhibidores de las Cdk; Cdc25C activa Cdk1 en M

Proteínas inhibidoras de Cdk

p27 Inhibe las actividades Cdk G1/S y Cdk-S en G1
p21 Inhibe las actividades Cdk G1/S y Cdk-S en G1 por daño al DNA
p16 Inhibe la actividad Cdk-G1 en G1; a menudo inactivada en cáncer

Ubiquitina ligasas y sus activadores

SCF Ubiquitinización de proteínas reguladoras implicadas en el
control de G1 (CKI)
APC Ubiquitinización de proteínas reguladoras implicadas en la
salida de la mitosis (ciclinas M)
Cdc20 Subunidad activadora del APC en todas las células
Hct1 Mantiene la actividad del APC tras la anafase y durante G1

Proteínas reguladoras de genes

E2F Activa la transcripción de los genes necesarios para la
progresión G1/S (ciclinas G1/S, ciclinas S y proteínas necesarias
para la síntesis del DNA)
p53 Transcripción de genes que inducen la detención del ciclo
celular (p21) o apoptosis en respuesta al daño al DNA
 5. La reproduccción sexual: Meiosis.
Concepto, fases y significado biológico
MITOSIS

→ Proceso de copia por el que un núcleo de una célula eucariótica

se transforma en dos núcleos hijos

→ Estos núcleos son genéticamente idénticos entre sí e idénticos al

núcleo a partir del que se han originado

MEIOSIS

→ División de un núcleo diploide para producir cuatro núcleos hijos

haploides

→ Reduce el número de cromosomas a la mitad

→ Para ello, se producen dos divisiones nucleares sucesivas y sólo

una duplicación de los cromosomas
Células haploides
y diploides en el
ciclo vital de
eucariotas

Figure 21-3. Haploid and diploid

cells in the life cycle of higher and
some lower eucaryotes. The
haploid cells are shown in red and
the diploid cells in blue. Cells in
higher eucaryotic organisms usually
proliferate in the diploid phase to
form a multicellular organism; only
the gametes are haploid, and they
fuse at fertilization to form a diploid
zygote, which develops into a new
individual. In some lower
eucaryotes, by contrast, the haploid
cells proliferate, and the only
diploid cell is the zygote, which
exists transiently after mating.
(Alberts et al., 2008).
 Primera división
celular de la meiosis

Sitio de
Bivalente recombinación génica

Figure 21-5. Events through the first cell

division of meiosis. For clarity, only one pair
of homologous chromosomes is shown. Each
chromosome has been duplicated and exists as
attached sister chromatids before pairing with
its homologous chromosome (homolog),
thereby forming a structure containing four
chromatids known as a bivalent. As shown by
the formation of chromosomes that are part red
and part black, chromosome pairing in meiosis
leads to genetic recombination between División
homologous chromosomes, as explained later.
(Alberts et al., 2008).
celular I de
la meiosis
 Estadíos de la profase en la meiosis I

Figure 14.33. Stages of the prophase of meiosis I Micrographs illustrating the morphology of chromosomes of the lily. (Cooper y Hausman, 2004).
 Recombinación
génica

Figure 21-6. Paired homologous chromosomes

during the transition to metaphase of meiotic
division I. A single crossover event has occurred
earlier in prophase to create one chiasma. Note that
the four chromatids are arranged as two distinct
pairs of sister chromatids. As in mitosis, the sister
chromatids in each pair are tightly connected along
their entire lengths, as well as at their centromeres,
by proteins called cohesins. The entire unit of four
chromatids is referred to as a bivalent. The
combination of the chiasma and the tight
attachment of the sister chromatids holds the two
duplicated homologs together. (Alberts et al., 2008).
 Recombinación génica

Figure 21-10. A bivalents with three chiasmata resulting from three crossover events. (B) In this drawing,
Figure 17-48. A crossover between chromatid 1 has undergone an exchange with chromatid 3, and chromatid 2 has undergone exchanges with
homologous. (Alberts et al., 2008). chromatid 3 and 4. Note that the sister chromatids of the same chromosome do not exchange with each other. (A)
Light micrograph of a grasshopper bivalent with three chiasmata. (Alberts et al., 2008).
 Comparación entre
meiosis y mitosis

Figure 21-5. Comparison of meiosis and mitotic

cell division. As in the previous figure, only one
pair of homologous chromosomes is shown. In
meiosis, after DNA replication, two nuclear (and
cell) divisions are required to produce the haploid
gametes. Each diploid cell that enters meiosis
therefore produces four genetically different
haploid cells, whereas each diploid cell that
divides by mitosis produces two genetically
identical diploid cells. (Alberts et al., 2008).
 Modelo actual de la regulación del ciclo celular

Figure 13-2. Current model for regulation of the eukaryotic cell cycle.
Passage through the cycle is controlled by G1, S-phase, and mitotic cyclin-
dependent kinase complexes (CdkCs) highlighted in green. These are
composed of a regulatory cyclin subunit and a catalytic cyclin-dependent
kinase subunit. Protein complexes (orange) in the Cdc34 pathway and
APC pathway polyubiquitinate specific substrates including the S-phase
inhibitor, anaphase inhibitor, and mitotic cyclins, marking these substrates
for degradation by proteasomes. These pathways thus drive the cycle in
one direction because of the irreversibility of protein degradation.
Proteolysis of anaphase inhibitors inactivates the protein complexes that
connect sister chromatids at metaphase (not shown), thereby initiating
anaphase. (Lodish et al., 1999).