Senescence is a major tumor suppressor mechanism that forms a barrier against tumorogenesis by limiting the number of times a cell can divide. Immortalization, which involves the activation of telomere maintenance mechanisms like telomerase or ALT, allows cells to bypass this barrier and divide indefinitely. This is an important step in carcinogenesis, though additional genetic changes are required for full malignant transformation. Senescence and immortalization play key roles in cancer development by respectively acting as a proliferation barrier and allowing for unlimited cell division.

1. ROLE OF SENESCENCE
AND IMMORTALIZATION
IN CARCENOGENESIS
By
B.C. Muthu bharathi II B.Sc(Biotechnology)

2. 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)

3. 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

4. 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

5. IMMORTALIZATION
 An important role in carcinogenesis is
reviewed
MARKER OF IMMORTALIZATION
 An activated telomere maintenance
mechanism
 Inactivation of p53 and of the Rb /p16INK4a pathway

6. TELOMERE HYPOTHESIS
 Clock mechanism is the progressive telomere
shortening
 It occur in cell division
TELOMERE AND REPETITIVE DNA

7. OLOVNIKOV’S HYPOTHESIS
During cell division
DNA is lost from ends of chromosome
Telomere length has decreased
Senescence occurs Olovnikov

8. TELOMERE SHORTENING
 The inability of the cDNA replication machinery
 activity of a putative 5′→3′ exonuclease
A. 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

9. 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

10. CONT…
 Very temporal correlation between Immortalization
and onset of telomerase Activity
 hTERT cDNA expression induce telomerase activity
 This permits cells to bypass senescence

11. ALT ACTIVITY
o Alternative Lengthening of Telomerase
o Any telomere in and ALT cell
can use its own DNA sequence
as template
o Telomerase positive cells contain
repressor ALT mechanism
RESULT:
 D-Loop formation
 Partial filling in C-strand
FOUND IN: Adrenocortical,breast,renal cell,
Osteosarcomes cancers etc.,

12. 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

13. 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

15. CONCLUSION
Immortalization
 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)