pRB Binds to the E2F Transcription Factor

G1 Cyclin CDKs Phosphorylate pRB

Sites of RB Missense Mutations in Tumors

AB

The A and B domain = pocket = where E2F binds

Tumorigenesis in RB Mutant Mice Requires E2F

Genotype Pituitary Tumors Thyroid Tumors

RB (+/-) 19/20 (95%) 10/19 (53%)

RB (+/-); E2F1 (+/-) 36/36 (100%) 2/34 (6%)

RB (+/-); E2F1 (-/-) 16/26 (62%) 0/22 (0%)

Yamasaki et al, Nat. Gen. 18:360 (1998)

Proliferation Signals

p16 RegulatespRB Phosphorylation

Tumor Type Annual Incidence Freq. p16 LossTotal Cases p16

Loss

Prostate 162.0 0.04 6.5

Breast 134.0 0.21 28.1

Lung, Non-small cell 106.6 0.64 68.2

Colorectal 66.4 0.27 17.9

Bladder 48.3 0.59 28.5

Lymphoma, non-Hodgkin's 37.7 0.33 12.4

Lung, Small cell 35.7 0.03 1.1

Head and Neck 31.7 0.68 21.6

Melanoma 31.1 0.65 20.2

Kidney 24.4 0.05 1.2

Endometrium 23.9 0.18 4.3

Leukemias 23.3 0.61 14.2

Pancreas 21.9 0.85 18.6

Ovary 16.2 0.25 4.1

Stomach 16.1 0.44 7.1

Thyroid 13.5 0.03 0.4

Esophagus 11.0 0.70 7.7

Multiple Myeloma 10.1 0.60 6.1

Other 158.5 0.20 31.7

Total 972.4 0.31 299.9

These estimates are derived only from analyses of primary tumors, and exclude cell line data.

Data Courtesy of Dr. Ned Sharpless

p16 is a Human Tumor Suppressor

Proliferation Signals

The Canonicalp16/pRB/E2F

“Pathway”

Sherr and McCormick, Cancer Cell ·2:103 (2002)

The RB Pathway in Human Cancer

(p16)