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Abnormal Apoptosis Implicated In Malignancy

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Abnormal Apoptosis Implicated In Malignancy
Author: Aurelian Udristioiu
Publisher: Emergency County Hospital TARGU-JIU
5 pages
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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  

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