Upload
bharathichellam
View
20
Download
0
Embed Size (px)
Citation preview
ROLE OF SENESCENCE AND IMMORTALIZATION
IN CARCENOGENESIS
By B.C. Muthu bharathi II B.Sc(Biotechnology)
WHAT IS SENESCENCE?
A major tumor suppressor mechanism Forms a barrier against tumorogenesis “Hayflick limit” Biochemical and Morphological Changes of
cell Less efficiency of cell in replacing and
maintaining cell components (Senescence cell remain active even though
proliferation is going on)
SENESCENT CELLS Enlarged Express pH dependent Galactosidase activity Cell lineage
SENESCENCE- A BARRIER AGAINST TUMOROGENESIS
Acquist the proliferation of unlimited no. of cell division
Essential for malignant transformation
HAYFLICK’ S FINDINGS
Senescence- Cumulative no.of cell division No. of cells required for development of tumors is much greater than Hayflick’s limit Leonard Hayflick
IMMORTALIZATION An important role in carcinogenesis is reviewedMARKER OF IMMORTALIZATION
An activated telomere maintenance mechanism Inactivation of p53 and of the Rb
/p16INK4a pathway
TELOMERE HYPOTHESIS Clock mechanism is the progressive telomere
shortening It occur in cell division
TELOMERE AND REPETITIVE DNA
OLOVNIKOV’S HYPOTHESISDuring cell division
DNA is lost from ends of chromosome
Telomere length has decreased
Senescence occursOlovnikov
TELOMERE SHORTENING
The inability of the cDNA replication machinery
activity of a putative 5′→3′ exonucleaseA. Increase in G-Rich strand than C-Rich strand
B. Requirement of RNA primer
C. Degradation of RNA primer
D. Infilling of terminal gap
E. 5′→3′ exonuclease degrades and additional 130-210 nucleotides
TELOMERASE ACTIVITY Contains RNA(hTR, hTER) &Protein subunits RNA subunits synthesis TTAGGG repeate DNA
OTHER PROTEINS TEP 1, p23, H3P90 form part of telomere complex
CONT… Very temporal correlation between
Immortalization and onset of telomerase Activity hTERT cDNA expression induce telomerase
activity This permits cells to bypass senescence
ALT ACTIVITYo Alternative Lengthening of Telomeraseo Any telomere in and ALT cell can use its own DNA sequence as templateo Telomerase positive cells contain repressor ALT mechanismRESULT: D-Loop formation Partial filling in C-strandFOUND IN: Adrenocortical,breast,renal cell, Osteosarcomes cancers etc.,
TERMINAL PROLIFERATION ARREST(TPA)
Inactivation of p53&Rb/p16
Inactivation of p53– Methylation of gene’s CpG Loss of pRb -- Expression of HPV E 7
oncoprotein in fibroblast
INK4a
Bypass senescence Crisis(Arrested)
Escaped cell becomes immortalised
GENES INVOLVED IN SENESCENCE AND IMMORTALIZATION
p53, p16INK4a, Rb
p14ARF and MDM2 which control p53 availability in the nucleus
p33ING1, which may be required for some of p53′s functions
CDK4 or a D-cyclin, or proteins such as the basic helix–loop–helix transcription factor Id-1 that may interact with factors required for function of pRb
Polycomb-group transcriptional repressor bmi-1 that coordinatelyregulates p14ARF and p16INK4a
CONCLUSIONImmortalization Prequisite for tumor Necessary but sufficient for malignant transformation Some cancers do not contain immortalization cells(Small cell
carcinoma of lungs-permanent cell lines) This is due to suboptimal cell culture
SENESCENCE - Major barrier to tumorogenesis IMMORTALIZATION- Not sufficient(Necessary for genetic
changes for malignancy)