THE GUARDIAN ANGEL OF GENOME P53 IN

CANCER TREATMENT BY

J.RAVINDER RAJU

DISCOVERY OF P53

In 1970 six investigators independently reported.

Named as “ Death star, guardian of genome,good and bad cop,master watchman & molecule of the year” (1993,science magazine )

Studies involving two approaches:

I)virologic approach II)serologic approach

.

Mutated/inactivated in >50% cancers

P53 located on chromosome 17p

P53-”Caretaker” system

Functions like brakes ,keep cell numbers down either by: 1)cell cycle arrest 2)promoting apoptosis

Structure and functions

Regulation of p53

ROLES OF P53:

HUMAN CANCERS AND P53 MUTATIONS:

More than 26,000 somatic mutation data of p53 in the IARC.

Frequency of p53 mutations varies from ~10 to 70%

Germ line mutations of p53 cause Li-fraumeni syndrome

Most p53 mutations in cancer within DNA binding domain

P53 based cancer therapies:Adenovirus based therapy ONYX 015:

Adenoviruses rely on their host cells to replicate

“ONYX 015” –modified adenovirusDeletion of E1B geneE1B proteins involved in production of cyclin E

for replicationE1B function is not required in cancer cells In cancer cells deregulation of cyclin E

observed

P53 based cancer therapies:

P51 gene therapy: 1st p53 gene therapy reported in 1996Retroviral vector containing wild type p53

geneUnder the control of actin promoter to treat

NSCLCViruses are engineered to lack early proteinsFew clinical trails reached phase III Recently p53 gene therapy has been

developing in china

P53 stabilization:MDM2 - E3 ubiqutin ligase which controls p53

degradationMany tumors over express MDM2,without p53

mutations For eg: nutlins acts as antagonists of MDM2-

P53 interactionM-219 is another molecule that stabilize p53

FUTURE OF P53:Although there have been 10,000

publications much is still unknownStill don’t under stand the micro

environmental conditions that favor the selection of cells with p53 mutations

Why the expression of wt p53 results in apoptosis in some cells, growth arrest in others