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Description:
-damage mechanisms. However, apoptosis is a normal process
which ensures the permanent renewal of cells, while autoimmunity is
an abnormal process that can lead to serious health issues [1].
Body of Review
The extrinsic pathway of apoptosis
Apoptosis is induced by the signal molecules – known as ligands –
which are released by other cells, and which bind to the trans-membrane
death receptors of the target cell. For example, the immune system’s
natural killer cells posses the Fas ligand (FasL) on their surface: the
binding of the FasL to Fas receptors (a death receptor) on various target
cells will trigger the aggregation of multiple receptors on the surface
of that target cell [2]. The aggregation of these receptors then leads to
the recruitment of an adapter protein, known as Fas-associated death
domain protein (FADD), on the cytoplasmic side of the receptors.
FADD, in turn, recruits caspase-8 (an initiator protein), forming the
Death-inducing Signal Complex (DISC).
The intrinsic pathway of apoptosis
The intrinsic pathway is triggered by cellular stress – specifically,
mitochondrial stress caused by various factors, such as DNA damage.
The stress signal will cause the pro-apoptotic proteins found in the
cytoplasm – BAX (pro-apoptotic, cytoplasmic protein) and BID – to
bind to the outer membrane of the mitochondria and signal the release
of the internal mitochondrial content.
However, the signal of BAX and BID is not enough to trigger a
full release of the mitochondrial content: BAK, a pro-apoptotic
protein found in the mitochondria, is also needed to fully promote the
mitochondrial release; it is important to note that the mitochondrial
content also includes cytochrome C. Besides cytochrome C, the
mitochondrial content released also contains the Apoptosis Inducing
Factor (AIF) which facilitates DNA fragmentation, preventing the
activity of the Inhibitors of Apoptosis (IAP) [3,4,30].
Caspase activity
Caspase activity in apoptotic cells may lead to a presentation of
cryptic epitopes or neo-epitopes to which the immune system is not
tolerant. Citrulinated, acetylated, and phosphorylated forms of antigens
may lead to increased immunogenicity. The initiator procaspase-9 is the
main upstream enzyme in the apoptotic cascade. Down the enzymatic
cascade, there is an amplification of the initial caspase activity until
the key reactions are reached: cleavage of proteins that normally hold
DNAase in its inactive form, cleavage of poly-ADP-ribose-polymerase,
cleavage of nuclear laminas.
Mitochondria have a fundamental position in executing apoptosis
induced by intracellular signals. When cells are stressed due to physical
signals, chemical stimulus, hypoxia, or cytokines, mitochondria release
pro-apoptotic proteins, including cytochrome C. Following its release
into the cytoplasm, cytochrome C forms a complex with the highenergy-
molecule, Adenosine Triphosphate (ATP) and with the enzyme
Apaf-1. In turn, this newly formed complex will activate caspase-9, an
initiator protein, which then interacts with the cytochrome C-ATPApaf-
1 complex to form an apoptosome. The apoptosome activates
caspase-3, the effector protein which then initiates the cellular
degradation (Figure 2).
*Corresponding author:
Aurelian Udristioiu, Emergency County Hospital Targu
Jiu, Clinical Laboratory, Gorj, Romania, Tel: +40 (723) 621 414; Fax: +40 (253)
210 218; E-mail:
aurelianu2007@yahoo.com
Received
October 21, 2011; Accepted April 18, 2012; Published
April 21, 2012
Citation:
Udristioiu A, Iliescu R, Udristioiu L, Cojocaru M (2012) A New Approach
of Abnormal Apoptosis Implicated in Malignancy and Autoimmunity. J Bioanal
Biomed 4: 034-038. doi:
10.4172/1948-593X.1000061
Copyright:
© 2012 Udristioiu A, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Abstract
Auto-reactive cells which escape from natural apoptosis represent a continuous threat of potential autoimmune
response. Abnormal apoptosis can play a role in negative selection of B and T lymphocytes that escaped the selfreactive
nature, and so, apoptosis could represent an additional source of auto-antibody. Increased activity of T cells
(CD3 +, CD4 +, or Th1 helper)) will, at a high serum level, cause a high expression of various types of inflammatory
interleukins: IL1-β, IL2. The most important regulatory mechanisms of apoptosis in T and B cells are: death receptor
cells, CD 95(Fas), TNF tumor necrosis, caspases, family Bcl-2 proto-oncogenes, Bax gene, p53 tumor suppressor
gene, and NF-κB nuclear factor of transcription and micro RNAs (miRNAs).The “decision” to undergo programmed
cell death is made only in the presence of extrinsic or intrinsic apoptotic messengers. Extrinsic inductors are ligands
– cytokines – that bind to death receptors (DRs) found on the cells’ surface, while intrinsic inductors come from the
mitochondria or from the nucleus cells.
A New Approach of Abnormal Apoptosis Implicated in Malignancy and
Autoimmunity
Aurelian Udristioiu
1*
, Radu Iliescu², Lucian Udristioiu¹ and Manole Cojocaru³
¹Emergency County Hospital Targu Jiu, Clinical Laboratory, Gorj, Romania
²Polytechnic Institute of New York University, Brooklyn, New York, 11201, USA
³Titu Maiorescu University, Faculty of Medicine, Physiol Fogy Department, Bucharest
Citation:
Udristioiu A, Iliescu R, Udristioiu L, Cojocaru M (2012) A New Approach of Abnormal Apoptosis Implicated in Malignancy and Autoimmunity.
J Bioanal Biomed 4: 034-038. doi:
10.4172/1948-593X.1000061
Volume 4(3): 034-038 (2012) - 035 J Bioanal Biomed
ISSN:1948-593X JBABM, an open access journal
Apoptosis as a cause for cancer
A dysfunctional apoptotic pathway may lead to the development
of cancers. Due to the sensitivity of the intrinsic pathway, tumors arise
more often through the intrinsic pathway than the extrinsic pathway
[5]. A very common cause of malignant tumors through the intrinsic
pathway is a mutation in the p53 protein (tumor-suppressor protein).
Besides regulating apoptosis, p53 also regulates the checkpoints of
the cell cycle, DNA repair, senescence, and genomic integrity [6]. A
mutation causes the p53 gene to lose any of its functions will inevitably
lead to carcinogenesis by letting the cell grow indefinitely, without any
regulation (Figure 1).
Another important factor in carcinogenetic process is the balance
between the pro-apoptotic and anti-apoptotic members of the Bcl-2
family. In a tumor cell, a mutation in the Bcl-2 gene results in increased
expression will suppress the normal function of the pro-apoptotic
proteins BAX and BAK, leading to malignancy [5]. On the other hand,
a mutation in the BAX or BAK genes can cause a down-regulation of
expression, causing the cell to lose the ability to regulate apoptosis,
once again, leading to cancer cells. The Inhibitor of Apoptosis (IAP)
family genes, which encode negative regulatory proteins, can prevent
apoptotic cell death (Figure 2).
In the normal cell, the p53 protein binds DNA, stimulating another
gene to produce a protein called p21, which interacts with a cell division
stimulating protein (cdk2) [11]. When p21 forms a complex with cdk2,
the cell cannot pass through to the next stage of cell division, and
remains arrested in G1 [7]. The p53 protein product of a
TP53
mutant
gene cannot bind DNA in an effective way, and as a consequence, the
p21 protein is not made available to act as the stop signal for the cell
cycle/cell division. Therefore, cells divide uncontrollably and form
tumors [4]. Not surprisingly, there is an increased frequency in the
amplification of the ubiquitin ligases protein (
MDM2)
involved in the
mechanism for the down regulation of p53 activity through ubiquitindependent
proteosomal degradation of p53 [36].
P53 has been shown to promote Hematopoietic stem cells (HSCs)
quiescence and self-renewal with recent studies showing that deficiency
of p53 likely promotes Acute myeloid leukemia (AML) by eliminating
its ability to limit aberrant self-renewal in hematopoietic progenitors.
Micro RNAs (miRNAs) are small non-protein-coding RNAs that
regulate gene expression by inhibiting the translation or catalyzing
the degradation of target mRNAs. Since the first miRNA,
lin-4
, was
identified in 1993, miRNAs have been shown to play critical roles in the
regulation of many biological processes including cell differentiation,
proliferation, and apoptosis, with significant influences on normal and
malignant hematopoiesis [32].
Given the many shared properties of HSCs and Leukemic stem cells
(LSCs), perhaps it is not surprising that these miRNAs that regulates
HSC function is also likely play important roles in the AML and LSC.
It is important to note, however, that while over expression of some of
these miRNAs in the normal hematopoietic system induces AML or
myelo proliferative-like disorders, none of the published studies to date
directly address the role of miRNAs in the LSCs [32].
In a study comparing expression of 154 miRNAs in 50 primary
AML samples with CD34+ cells, selected hematopoietic progenitors,
miR-34a
was found to be up regulated. This is an intriguing observation,
since
miR-34a
has been identified as a P53 target with pro-apoptotic
functions. Thus, it is interesting to speculate that
miR-34a
may
regulate p53 activity, thereby contributing to leukemic stem cells (LSC)
development, quiescence, or resistance to therapy. Given the many
shared properties of HSCs and LSCs, perhaps it is not surprising that
these miRNAs that regulate HSC function also likely play important
roles in the AML and LSC. It is important to note, however, that while
over expression of some of these miRNAs in the normal hematopoietic
system induces AML or myelo proliferative-like disorders, none of the
published studies to date directly address the role of miRNAs in the
LSCs [33].
The Myelodysplastic syndromes (MDS) are associated with a risk
for progression to AML, and recent studies have suggested a role
for miRNA dys-regulation in this process. A common subtype of
MDS characterized by an interstitial deletion of chromosome 5q is
characterized by refractory anemia, variable neutropenia, and a normal
or high platelet count with megakaryocytic dysplasia. Starczynowski
Chromosome 17
G0 G1 S G2
DNA
repair
Irreversable Bax
DNA
Damage Bcl-2
Summary
CAMP
Protein
Kiraza C
Survivire Ca
pd
P21 P53
Figure 1:
The p53 gene has been mapped in chromosome 17. In the cell, p53
protein binds DNA, stimulating another gene to produce the protein p21 that
interact with cycle cell in division, stimulating a protein of stop division (cdk2).
Regulators
JNK p38
Erk ATM
HIPK2
MDM2
p53
(activated)
p53
(Basal)
KAT5
p300
SET7
SMYD2
PRMT5
MDM2
MDM4
CD44
BAX
MLH1 SESN1
p21
or SET9
</span
About the publisher:

- My Book written in Clinical Laboratory Medicine, “ Hematological and Metabolical Aspects from Laboratory Medicine” , confirm the aria of my interest in discovery of carcinogenesis mechanisms, especially in onco-haematology field, Leukemia.
Seller www.amazon.com
Also, my new e-Book: e-BOOK: Hematological and Metabolical Aspects of Laboratory Medicine (Hematological and Metabolical Aspects from Laboratory Medicine) ( Second Edition ) [Large Print] [Paperback].
Publisher: Aurelian Udristioiu, 2 edition (September 9, 2013) Full Color on White paper, 122 pages. ISBN-13: 978-1492186816 (CreateSpace-Assigned) ISBN-10: 1492186813, BISAC: Medical / Laboratory Medicine, USA. Sold by www.amazon.com
Please, see the Blog of my Medical Book : http://aurelianudristioiu.blogspot.com
Thanks.~!
RECENT WORK OF RESEARCHES
1. Udristioiu A. The Assessment of Uncertainty in Measurement of Cholesterol; A Model of Calculation. Biophysical Journal; Volume 96, Issue 3, Supplement 1, February 2009; Page 504a.
2. Udristioiu A, Florescu Cristina, Popescu Manuela Andrei. “High Concentration of anaerobic ATP implicated in aborted apoptosis from CLL”. LabMedicine, American Journal of Clinical Pathology-ASCP, Manuscript 09-08-LM-S-SCI-0122R1, Published in 04-05/2010.
3. Aurelian Udristioiu. First Hematological Signal of Latent Anemia to Aging Population. Nature Publishing Group. Advance Search 0.1038 npre 2009.3285.1. Creative Common Attribution 3.0 License, accepted for the work online posted.
4. Udristioiu A, Cojocaru M, Florescu C. Screening Tests for Latent Anemia in Hospitalized Adults Over 65. LabMedicine, American Journal of Clinical Pathology-ASCP, Manuscript 09-11-LM-S-SCI-0156.R1, Published in 07-05/2010.USA American Journal of Clinical Pathology p-ISSN: 0002-9173 ICV 38.53 LabMedicine ; Ascp Press) , Impact Factor ISI, IF = 2.853 , 18 Index Copernicus Journals Master List 2006.
5. PHENOTYPIC AND GENOTYPIC CHARACTERIZATION OF ANTIBIOTIC RESISTANCE PATTERNS IN ACINETOBACTER BAUMANNII STRAINS ISOLATED IN A ROMANIAN HOSPITAL. MANUELA-ANDA RADU-POPESCU1*, SILVIA DUMITRIU2,SIMONA ENACHE-SOARE3, GABRIELA BANCESCU2, AURELIANUDRISTOIU4, MANOLE COJOCARU5, CODRUTA VAGU6
1 University of Medicine and Pharmacy “Carol Davila, Faculty of Pharmacy, Department of Microbiology, Traian Vuia 6, Sect. 2, 020956,Bucharest, Romania. 6“Stefan S. Nicolau” Virology Institute, Bucharest, Romania. FARMACIA 2010; (57); 3: 420-427 IMPACT FACTOR ISI THOMSON 0.144 .
6. Moleular Biological Tchiniques user for identification of Candida SPP. MANUELA-ANDA RADU-POPESCU1*, SILVIA DUMITRIU2, SIMONA ENACHE-SOARE3, AURELIAN UDRISTOIU4. 1 University of Medicine and Pharmacy “Carol Davila, Faculty of Pharmacy. FARMACIA 2010; (58); 4: 422-429
7. Udristioiu A. Role of Mg2+ ion as cofactor ATP in assurance of energetic environment cells( Abstract). Magnesium Research 2011; 24 (1): 22-6.
8. -Aurelian Udristioiu, Radu G. Iliescu, Cristina Popescu. Variability of bilirubin values in serum samples with high triglycerides; interference or congenital liver syndromes. J Biosci Tech Volume 2, Issue 4 (JULY 2011).
9. Aurelian Udristioiu¹*,Radu G. Iliescu², Lucian Udristioiu¹ and Manole Cojocaru. A new approach of abnormal apoptosis as a cause of autoimmunity and malignancy. Biotechnology and Molecular Biology Review Vol. 6(8), pp. 166-171, November 2011 . Available online at < http://www.academicjournals.org/BMBR>
10. Aurelian Udristioiu, Cristina Popescu, Manole Cojocaru, Sorina Comisel, Valentina Uscatescu. Relation between LDH and Mg as Factors of Interest in the Monitoring and Prognoses of Cancer. Journal of Bioanalysis & Biomedicine. Ref.: Ms. No. JBABM-11-48R1 accepted on Jan 27, 2012
11. UDRISTIOIU A. Florescu C, Popescu C, Cojocaru M "Significance of Neutrophil Alkaline Phosphatase versus Isoenzymes ALP in Acute or Chronic Diseases,"accepted for publication in LabMedicine, LabMedicine Manuscript 11-03-LM-U-MR-0052.R2/11/12/2011.
12. Aurelian Udristioiu¹, Radu Iliescu ², Manole Cojocaru³. Errors in Counting Platelets in Hemodialysis Patients by Use of Optical Microscopy. Review of Applied Physics (RAP) Volume 2 Issue 1, March 2013; p: 17-22
13. Aurelian Udristioiu¹, Radu Iliescu ², Manole Cojocaru³. Energetic Levels of Metabolic Pathways in Malignant B and T Cells Mini-Review. Advances in Chemical Science Volume 2 Issue 4, December 2013; 2; 90-95
14. Aurelian Udristioiu¹, Manole Cojocaru² Hemolytic Anemia Drugs Induced by Antihypertensive Agents: A case of Laboratory. 13 Scholars Journal of Medical Case Reports ISSN 2347- 6559. Sch J Med Case Rep 2013; 1(1):8-11
15. Aurelian Udristioiu1*, Radu G. Iliescu2, Manole Cojoraru Molecular mechanisms of bone reconstruction in new dental implant technology. Integrated Journal of British. Volume 1 2014 Issue 1(5-6), pg: 1-7; IJBRITISH.
WRITEN BOOKS:
1.Aurelian Udristioiu. Cicloergometrul si Sanatatea. Ed. Medicala 1990, Bucuresti. ISBN: 973-39-01105-9; Formatul 16/10 x 100; Nr pagini: 78.
2.Aurelian Udristioiu. “Bioenergetica Celulara si Maligna” Ed. Academica Brancusi 2002, Targu Jiu, Bun de tipar, Bucuresti, Tipografia Everest 2001; ISBN 973 85342-6-7; Formatul 16/14 x 100; Nr. Pagini: 307.
3. Aurelian Udristioiu, Manole Cojocaru, Radu Iliescu., Hematological and Metabolic Aspects from Laboratory Medicine" (ISBN 978-3-8473-0775-4). LAP LAMBERT Academic Publishing GmbH & Co. KG Heinrich-Böcking-Str. 6-8 , 66121, Saarbrücken, Germany, 2012.
4. Book title: Renal Diseases / Book 2 (ISBN 979-953-307-704-7). Chapter title: Variability of Biological Parameters in Blood Samples between Two Consecutive Schedules of Hemodyalsis
Authors: Aurelian Udristioiu, Manole Cojocaru, Victor Dumitrascu, Daliborca Cristina Vlad, Alexandra Dana Maria Panait and Radu Iliescu, Publishing Group 2011., Volume 2, Issue 4 (JULY 2011)
5. e-BOOK: Hematological and Metabolical Aspects of Laboratory Medicine (Hematological and Metabolical Aspects from Laboratory Medicine) ( Second Edition ) [Large Print] [Paperback].
Publisher: Aurelian Udristioiu, 2 edition (September 9, 2013) Full Color on White paper, 122 pages. ISBN-13: 978-1492186816 (CreateSpace-Assigned) ISBN-10: 1492186813, BISAC: Medical / Laboratory Medicine, USA. Sold by www.amazon.com