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)