p53 THE TUMOR SUPPRESSOR

Presented bySpoorthi shridhar MSc. biochemistry

INTRODUCTION

• Tumor Suppressor

• 53 kDa protein

• Encoded by TP53 gene

• Regulates cell cycle

HISTORY• 1979 - David Lane and Lionel Crawford

• 1983 - The term “p53” was coined

• p53 acknowledged as an oncogene

• 1984 - David Wolf and Rotter

• 1989 - p53 tagged as a tumor suppressor

STRUCTURE

AMINO TERMINAL DOMAIN transactivation transcription factors – MDM2

PROLINE-RICH REGION stability

CENTRAL CORE DNA binding domain

C-TERMINAL DOMAIN negative regulation

STABILITY OF P53

ACTIVATION

PHYSICAL AGENTS: UV, gamma, X-rays

CHEMICAL AGENTS: carcinogens chemotherapeutic agents alkylating agents

OTHER CAUSES hypoxia heat shock

FUNCTIONS

activation in response to stress stimuli

prevents inappropriate cell proliferation: cell cycle arrestapoptosis

CELL CYCLE ARREST IN G1 PHASE

Molecular Biology Of The CellBruce Alberts

CELL CYCLE ARREST IN G2 PHASE

p53

Gadd 45 CDK1

Cyclin B/CDK1

Prevents phosphorylation

APOPTOSIS

MUTATIONS

LUNG CANCER:

• 33% in adenocarcinomas to 70% in small cell lung cancers

• GC to TA transversions• Exogenous carcinogens such as benzopyrene • Codons 157, 248 and 273

UV AND SKIN CANCERS:

• CC to TT transitions• Codons 245 and 247/248

COLORECTAL CANCER:

• 34% proximal colon tumors• 45% distal colon and rectal tumors

Molecular Cell Biology

Lodish Et al.

THERAPEUTIC APPLICATIONS

• Inhibiting interaction of MDM2 with p53

• Small molecule inhibitors: nutlins

• Antisense oligodeoxy nucleotides

• Inhibiting E6 protein of Human Papilloma Virus

• Leptomycin B and Actinomycin D

• Induction of apoptotic pathways

• Introduction of wt p53 gene into tumors

GENE THERAPY:

• 2004 - treatment of head and neck cancer in China

• McCormick and co-workers, USA - infection of the tumor with recombinant adenovirus.