How
Does Cancer Affect Normal Cell Functioning
Abstract
Motivation:
the term cell cycle is commonly
depicted as uncontrolled multiple division of the cell in result proliferation of
cells that change into a malignant tumor form. This cell outgrowth produce metastasis .the past several
years witnessed that cancer play a
dramatic role in destroying the life of peoples so a lot of work done on ontogenesis
clinically as well as in drug making industries. Cancer cells encompass a series of missteps that change a normal cell into proliferative tumor cells, which also affect surrounding cells. There
are various cell cycle, regulators
which control division of cell cycle
but when they are disturbed or deregulate then a normal working cell transformed
into tumor cells. Series of checkpoints are involved in controlling cycle cell but aberrations of these
checkpoints provide an opportunity for Cancer
cells present study is conducted to find out and summarize all work done on
Cell cycle and oncogenesis.
Implications: So Cancer
can be controlled by multiple steps
and checkpoints .there are two main regulators which are involved in
controlling cell cycle are
retinoblastoma protein RB and P53 transcription factor which is also called
guardian of the cell cycle. other checkpoints involve in the cell cycle are Cyclin-dependent kinase (CDK) Complex of protein which is either
directly or indirectly involved in cell progression, deregulation of these the complex of protein notice in mutated cancer
cell
Introduction
Cell
cycle phases and control: Cell division consist of series
of steps that lead towards duplication of DNA for production of daughter cell, it’s an important process by which a single cell duplicate itself
and fertilized egg develop into a
complete adult individual. The division process is very necessary for development
of various internal parts of the body such as hair, nail, blood cells, brain cell etc.,
but any sort of imbalance and deregulatory damage the whole division process. Cell
during division enters in distinct four phases G1,,S ,G2,M phase. (Pardee AB,
Dubrow R .1978) G1 ( Gap 1 ) S( Synthesis phase,G2 ( Gap 2 phase)are
collectively called as interphase, M phase is called as Mitosis phase .the
period between mitosis also term as interphase in which DNA Replication took place in S phase(Baserga R,1985). Mutated cancerous cells show various features
in which cell damage. insensitive to
medicine, the proliferation of surrounding cells, decreased of checkpoints activity(Hanahan D. and Weinberg
,R.A 2000).,In S phase DNA duplicate
itself and exact copy of DNA form,G1 ,G2 both
gap phase in which cell prepare itself for a different type of metabolic
activity, different enzymatic reaction also take place. various checkpoints
are available which monitor the growth activities of cells as well as the length of
phases. Cells have another temporary
phase in which cells enter for a short time ,stop to divide itself called the Go
phase, this phase also called the resting phase. Different events show that
mutation and deregulatory in these checkpoints disturb the normal division of the cell. he prevention of human cancer
(Moon Taek Park and Su-Jae
Lee.2003).
Different cyclins and different Cdk
complexes proteins are expressed
in the whole-cell cycle at different
points that check and maintain cell cycle (Nigg,1995).following diagram show
the stages and description of their
activities (Kathleen et.al figure
show the process of replication of DNA and
division of the cell in series,,these are coordinated steps ,Coordinated the mechanism is control by Cascade of
kinase protein which is phosphorylated.one step control next upcoming step.
this is a high kinase activity. 2nd regulatory step is CDKs which is
strictly monitor the cell cycle
process, but if there is flaw occurs in regulatory checkpoints then it will be
harmful for replication of DNA process as well in Segregation of Chromosomes.
Cell cycle
machinery control the mutation process as well as proliferation of cells,
because Cancer is a disease of
proliferation in which uncontrolled division of cell take place cells not able to perform function well and
insensitive to drugs and genes in mammals there are different CDKs bind to
various types of CDKCs ,which are known as Cdk1 (first human Cyclin-dependent
kinase protein identified),it is also associated with Cyclin A /B. There are
also other mammalians Cdk 2,Cdk4 ,Cdk6. These are regulatory check points
control the cell cycle at different
phases of cell cycle .but the CDKs
remain same and specific in cell cycle but the level of Cyclin vary, which lead towards progression in cell cycle.
Figure
2:
expression of Cyclin A, B, D and E during G1, S, G2 phases of the cell cycle (waehrend_Zellzklu et.al,
2011).
Family
of protein that inhibits Cyclin-dependent kinase ( CDKs) are termed as Cyclin-dependent kinase inhibitor CDKI play a vital role in progression of cell cycle. Subfamily (MTS1, MTS 2, P 18) of these
complex CDKI proteins has homology with the tumor-suppressing gene. The subfamily
proteins are structurally and functionally similar to tumor-suppressing genes.
Another factor which regulates the cell cycle
and mutation in this checkpoint plays a vital role in the development of Cancer. Cellular Senescence is a
phenomena in which permanent form of cell
cycle cease, which can be triggered by DNA damaged as well as activation of
oncogenes( Lowe SW , Cepero E, Evan G.,2004)
p53 also depicted as TP53, also
called as tumor protein because it is the gene that regulates and maintain cell
cycle hence function as tumor suppression,p53 has a great role in conserving stability by preventing
mutation in the genome ( Strachan and Read ,1999) , cellular senescence has been
using in response to anti-tumor treatments.
If the p53 gene damaged then the tumor
suppression is reduced, few people inherit one functional copy of p53 will most
likely develop a tumor in adulthood, a disease called Li –Fraumeni Syndrome. In
health p53 is regularly produced and then also degrade in Cell, but this is associated with MDM-2 (which is own regulatory
gene).p53 has also play role in DNA repair and apoptosis (cell death). p53 activates the target genes which are Apaf1 and Bax
.apoptosis can be induced by binding
with cascade protein caspase 9,but this
is done in a situation to avoid the proliferation of cell which containing damaged
,mutated DNA otherwise Cell lead to Cancerous.
Related Work
Cancer research in the last few
decades has generated complex knowledge, revealing cancer a disease which involves a change in genomic sequence. These
changes produce due to loss of suppressor genes, alternation of recessive genes
loss of function. two classes of Cancer
genes identified through alternation in
human as well as animal cancer by depicting cancer phenotypes in experimental models ( Bishop and
Weinberg,1996). Pathological analysis of various organ sites expose lesions
that represent the intermediate steps in a process in which normal cells
transformed into premalignant sites into
invasive cancer (Foulds 1954).Cancer cell genotypes is a tangible
of six alternations in cell
physiology which collectively Commands malignant
growth of cell and mutate the function
of the cell cycle . There are at least
four mechanisms by which the normal mutation rate could lead to mutations
leading to tumor progression without assisting
an increased mutation rate in cancers.
Firstly, cancer-causing genes could
contain sequences that mutate at exceptionally high frequencies. Mutagenic hot
spots have been found in a variety of genes (Coulondre, C., and Miller, J.H
,1977) though mutational activation of ras genes can occur at multiple sites,
mutations in cancers are commonly
observed at only a few sites (Barbacid,1987). It is not known whether the
localization of mutations to specific nucleotides in ras genes results from an
increased rate of DNA damage, or destroy DNA repair, or an elevated frequency
of misleading by normal DNA polymerases opposite unrepaired lesions, or from
the selective building up of cells refuge specific ras mutation mutations which
lead to frank cancers could have
multiple causal origins. Both spontaneous and chemically incorporate mutations
could contribute to tumor progression. The 100-fold higher incidence of human cancer in the large intestine compared
to that in the small intestine could reveal the part of carcinogens produced
within the large intestine by the bacterial flora. Although the cell turnover
rate is slightly greater in the small intestine, the track from stem to discriminating
cells may be complex and different in the small and large intestines. Most
vitally, premalignant changes in cells may not be manifested due to the
constant shedding of cells into the intestinal lumen. a multifactorial scheme
could present for the presence of large numbers of mutations in single cells.
However, chemically induced DNA damage does not coinciding the sequential
chromosomal changes that features the process of tumor progression. Unrepaired
DNA damage could participate in quiescent cells and be amenable for a large
number of mutations at the first cell division, but the DNA harm would not be
present in tumor cell progeny .the evolutionary process show that CDK family in
mammals divide into subfamilies (cdk1, cdk4, and cdk5), it also divides into
five transcriptional subfamilies which are (Cdk7, Cdk8, Cdk9, Cdk11 and, Cdk
20), mostly these Cdks bind to one more than one cyclins. These proteins are an important feature of several diseases, which include Cancer and various drugs used in clinical trials. CDKs have to be
activated and inactivated in a complex way at a specific point during the cell cycle .such mechanism of CDKs was
first time analyzed on the maturation promoting factor also called as Cyclin
B/Cdc2 complex. its activity is a vital process foe entering in M phase. Cyclin B
accumulate throughout the G phase.it form a complex and undergoes to a process
called phosphorylation by cdc2 activating kinase (CAK) , TFIIH is also
responsible for phosphorylation(Feaver W et.al,1994). (Roy R et.al, 1994).mammals
use a different type of Cdks and cyclins, among CDK D are associated with CDK 4
and CDK 6,but in hematopoietic cells CDK 6 are more prominent during G1 phase.
Cyclin D 1 is predominant in the murine macrophage cell line .Cyclin E is also
operating in the G1 phase Cyclin D also associate with CDK 2,the kinase
activity is at peak during this stage, but if the level of Cyclin D or Cyclin E minimize the span of G1 phase in fibroblast
.but if the Cyclin D inactivate then cell do not enter in S phase. (OhtsuboM et.al, 199).Kinase activity also
necessary for cell cycle continuity,
but when cell enter in S phase the level of Cyclin E decrease, with the
decreasing level kinase activity also cease. Rendering of cyclin A activity in
mammalian fibroblast during the G phase either by antibody or si RNA result in the
inhibition of DNA synthesis (Pagano M, 1991).
Role of Rb protein in cell cycle
and Cancer
Rb
is another protein which shows its effects in the cell cycle and cancer
.the phosphorylation of Rb protein is highly monitored during cell cycle .but during the G1 phase Rb
occur as phosphorylated or UN phosphorylated form. The phosphorylation status
of Rb is tightly monitored during the late G1 through the end of M phase, it is
relevant phosphorylated .the RB protein is bind to cellular transcription
factors which are depicted as E2F, these have five contiguous related proteins
E2F-1,E2F-2,E2F-3,E2F-4 and E2F-5 .its depicted as tumor suppressor
protein that is dysfunctional in some major form of Cancer .( Murphee AL,1984)the
most important function of Rb is
to prevent excessive cell cycle
growth by restrain cell cycle progression .when this protein is absent cell
progression start and cell undergoes proliferation Rb gene also control chromatin
remolding enzymes which are acetylases and methylases.( Shao Z, Robbins PD,1995).Rb bind and inhibit the
transcription factors of E2F Family
which are composed of a dimer of E2F protein and dimerization protein (Zukerberg
LR,1995).when it is time of cell to wriggle into S phase,CDKs and Cyclin phosphorylates Rb to pRb form,
restrain its activity. The inceptive phosphorylation is performed by Cyclin
D/CDK4/CDK6 and followed by additional phosphorylation by Cyclin E/CDK2. PRb
remains phosphorylated all aspects to S, G2 and M phase and Inactivation of pRb
during embryogenesis foster inappropriate cell
cycle activity. This follows from the ingenue of pRb in negatively
regulating entry into the cell cycle.
In distinction to apprehension, however, the increased cell cycle activity in Rb null mice does not crop in a net increase
in cell number. This is due to a
commensurate increase in cell death that precisely eliminates the abnormally
cycling cells. This cell death
(apoptosis) often debased on the function of p53, as authenticate from the
analysis of RB/p53 double-mutant embryos.
Figure4.
Schematic representation of cell cycle
and machinery (Toshiyasu et.al, 1995)
Recent
research prove clinical target in a
prostate cancer as well as in breast
cancer, the majority of AR contains
unique functions , ER-negative tumor get advantage from the combined target of AR
and the ErbB2 /HER2 oncogene.it also play a role in metastatic disease. AR is a
protein receptor which binds to ligand.it has C-N terminus it has functional
domain AF-1 and AF-2. AF-1 is transactivation factor and AF-2 is highly
conserved protein. androgen is very essential for normal growth in female but
during the postmenstrual cycle level
of estrogen fall down, the binding of
androgens to the LBD cause
conformational changes due to homodimerization AR move to the nucleus, bind the AREs and regulate
gene transcriptions factor (Mononen N et
al.2002). mutation occur Mutations
occurring in the growth signaling network
result in the loss of proteins which function to suppress oncogenes
, which cause deregulation of cell cycle
.this disturbance results in the proliferation of cell cause cancer.(Gareth
H Williams and Kai Stoeber,2012).PTEEN is a tumor-suppressing gene present on
the chromosome 10q23 ,which encode a
protein as well as phospholipid phosphatase .there are number of mutation which
are somatic in human malignancies. The activity of ILK is coincidently increase
in a serum- and the harbor-independent manner in PTEN-mutant cells, and
transfection of wild-type (WT) PTEN into these cells cease ILK exertion.
Transfection of a kinase-deficient, dominant-negative form of ILK or
Manifesta to a small molecule ILK inhibitor suppresses the constitutive
phosphorylation of PKB/Akt on Ser-473, but not on Thr-308, in the PTEN-mutant
prostate carcinoma cell lines PC-3 and LNCaP. Transfection of dominant-negative
ILK and WT PTEN into these cells also results in the inhibition of PKB/Akt
kinase activity. Furthermore, dominant-negative ILK or WT PTEN indulge G1 phase
cycle arrest and increase apoptosis. Together, these data authenticate a
critical role for ILK in PTEN-dependent cell
cycle regulation and survival and indicate that inhibition of ILK may be of
significant value in PTEN-mutant tumor therapy
Proliferating
cells undergo a metabolic reprogramming to “aerobic glycolysis” in which
glycolytic fluctuation boost up oxidative phosphorylation is superseded,
pyruvate is neophyte primarily to lactate, and intermediates of the TCA cycle are
diverted into anabolic pathways to facilitate cell growth (Vandar Heiden et
al,2009) A similar metabolic switch to aerobic glycolysis, termed the Warburg
effect is also analyzed in tumor cells, and recent studies suggest that p53
normally inhibits this process by limiting glycolytic fluctuation through
various mechanisms ( Feng and Levine,
2010; Warburg, 1956).
; from
the above-cited study it is clear that cancer
cells behave in a different way as compared to cancer cells. Cancer cell
multiply very rapidly and affect other cell in metastatic way. Cancer cells have their Replicative
mortality” so they fail to undergo the programmed cell death processor
apoptosis.one cell might get mutated and give rise to a malignant tumor. And
invade other tissue Development and Progression are due to disturbance of cell cycle regulator which are CDKs and
Different kind of Cyclin protein, several proteins that transmit growth factor
signals are coded by proto-oncogenes .if one of protein absent or become
overproduce it may lead to transmitting signal even in a situation when no growth the factor is available .the Ras protein are also encoded by proto-oncogene. Cancer-causing mutation often changes
the Ras protein which leads to an inactive form. there are another tumor suppressor proteins are present which monitor the cell
cycle but inactivation of pRB and
p53 result in dysfunctioning of protein
which shift normal cell to cancer.p53
called the guardian of the cell,so its absent cause damaging od DNA replication
.cells homozygous p53 mutation cause
Li-Fraumeni disease,(Yien et al,1992), but many discoveries and studies
on cell cycle and cancer do not come only from human but
research also stress on cell cycle regulation
on Zebrafish, Yeast, Drosophila. Different regulators checkpoints which
control the cell cycle process are androgens,
cyclins, CDKs, CDIs. estrogen receptors and tyrosinase.it is very necessary to
discover various drugs for control target genes which proliferate cancer .there is lot of discoveries and
work done cell cycle for complete
understanding as well for the discovery of drugs being used for treatment of cancer.it is a time to elucidate and
focus on the drug industry also for coping with such harmful disease.
Conclusion
Cancer is not a one disease
but is a complex form of many diseases. There
is a lot of work done in this field. Researchers have very curious about the
actual facts of Cancer .information
are beings continually added in research of cell cycle which is also aspirant
for others in the research and medical field. The recent advancement in
genetics, immunology is paving the way and explore a new method to control
target affecting genes .and perhaps develop various cures for Cancer. Researchers have developed a
breakthrough new treatment to get cancer
cell and kill themselves. The new development allows treatments to specify
target cells and genes. The study of how blocking of certain Proteins which might
cause Cancer. There is a need to
prepare more and more anticancer drugs
and enhance research in novel therapies. It’s a need of time to develop more
key genes which control cancer and
become a hope for cancer patients.