Transcript Tumor Suppressor Genes

Tumor Suppressor Genes
Folder Title: Suppress
Updated: April 5, 2007
TtlOffGn
Genetic Aberrations in Cancer:
What Can Go Wrong?
Inherent or Induced Initial non-Random Genetic Instability
Progressive Random Genetic Instability
Point Mutations and Failure to Repair DNA
Translocations and Inversions of Chromosomal Material
• To Where?
• Next to What? Activated?, Repressed? Amplified?
• Fused to What? Mis-regulated?
Deletions
• Of Entire Chromosomes
• Of Parts of Chromosomes
• Of Specific Genes
Additions
• Aberrant Chromosome Replication: Trisomy & Aneuploidy
• Amplifications and Repeats
GoWrong
Specific Genetic Abnormalities
Associated with Specific Cancers
Chronic Myelogenous Leukemia Reciprocal Translocation, 9&22
Burkitt's Lymphoma
Reciprocal Translocation, 8&14
Myelodysplasia and Acute
Myelogenous Leukemia
Trisomy 8
Meningioma
Monosomy 22
SpecCx
Chromosomal Deletions Associated with Specific Neoplasms
1p
Melanoma, Neuroblastoma,
Thyroid Cx, Ductal Breast Cx
Multiple Endocrine Neoplasia
Breast Carcinoma
Small-cell Lung Cx, Renal Cell Cx,
Cervical Cx
Familial Polyposis Coli, Colorectal Cx
Wilm's Kidney Tumor, Breast Cx,
Rhabodmyosarcoma, Bladder Cx
Retinoblastoma, Osteogenic Sarcoma
Small-cell Ling Cx, Ductal Breast Cx
Small-cell Lung Cx, Colorectal Cx,
Breast Cx, Osteosarcoma
Neurofibroma
Colorectal Cx
Menigioma, Acoustic neuroma,
Pheochromocytoma
1q
3p
5q
11q
13q
17p
17q
18q
22
From: JNCI, 83:92 (1991)
GenLost1
Oncogenes & Cancer:
Some Uncomfortable Facts &
Questions (Part 1)
• Some cancers involve loss of chromosomes,
loss of heterozygosity, loss of genes.
• How can losing an oncogene cause a cancer?
OncProb1
Oncogenes & Cancer: Some Uncomfortable
Facts & Questions (Part 2)
• If a malignant cell is fused with a normal
non-malignant cell, the hybrid cell is often
non-malignant.
• How can the malignant phenotype be
recessive in the cancer cell, if malignancy is
caused by the presence of an oncogene?
OncProb2
Oncogenes & Cancer: Some Uncomfortable
Facts & Questions (Part 3)
• Pre-disposition to some cancers is heritable
in a Mendelian dominant manner.
• If an oncogene causing cancer is being
inherited in the germ line, wouldn't that be
a lethal in the developing fetus?
See Sidebar 7.5, p. 226 in
Weinberg
OncProb3
Oncgenes & Cancer: Uncomfortable
Facts & Questions (Part 4)
• About 15 to 30% of human cancers are
associated with oncogene expression.
• What is the genetic basis for the other
human cancers?
OncProb4
Oncogenes & Cancer: Some Uncomfortable
Facts & Questions (Part 5)
• In spite of constant cell-division throughout
life, "only" one person in four presents with
a cancer during their life-time.
• If cancers are caused by turning on one of
thirty or forty oncogenes, why aren't there
more cancers?
OncProb5
The Likely Answer:
From Harris and Knudsen
Some cancers must be associated with loss of genetic
functions.
• There must be genes and gene products that
normally prevent cancer from being expressed.
• There must be tumor suppressor genes and tumor
suppressor proteins.
MustStop
Genetic Aberrations in Cancer:
What Genes are Messed Up?
What gene has been mutated, amplified,
derepressed, activated, fused and mis-regulated,
repeated?
What is it product, and what does that product
normally do?
CancerGenes or Oncogenes
What gene has been inactivated, repressed, lost?
What is its product, and what does that product
normally do?
Suppressor Genes or Anti-Oncogenes
WhoWrong
Chromosomal Deletions Associated with Specific Neoplasms
What's Missing?
1p
1q
3p
5q
11q
APC*
WT1
13q
Rb1
17p
p53
17q
18q
22
NF1
DCC
Melanoma, Neuroblastoma,
Thyroid Cx, Ductal Breast Cx
Multiple Endocrine Neoplasia
Breast Carcinoma
Small-cell Lung Cx, Renal Cell Cx,
Cervical Cx
Familial Polyposis Coli, Colorectal Cx
Wilm's Kidney Tumor, Breast Cx,
Rhabodmyosarcoma, Bladder Cx
Retinoblastoma, Osteogenic Sarcoma
Small-cell Ling Cx, Ductal Breast Cx
Small-cell Lung Cx, Colorectal Cx,
Breast Cx, Osteosarcoma
Neurofibroma
Colorectal Cx
Menigioma, Acoustic neuroma, Pheochromocytoma
From: JNCI, 83:92 (1991)
* Added 2003
GenLost2
Proposed
Role for
APC Protein
in Mitosis
APCMitosis
Familial Adenomatous Polyposis Coli
Figure 7.22 The Biology of Cancer (© Garland Science 2007) p.
226
Figure 7.10 The Biology of Cancer (© Garland Science 2007)
p. 219
Figure 7.6 The Biology of Cancer (© Garland Science 2007) p. 216
Figure 7.5a The Biology of Cancer (© Garland Science 2007)
p. 215
Properties and Functions of the Rb1 Gene
Product: pRB
105 Kd Nuclear Phospho-protein
• Hypo-phosphorylated:
Binds E2F Transcription Factor
Represses Cell Cycle
• Hyper-phosphorylated:
Releases E2F Transcription Factor
Releases Cell into Cycle
Phosphorylated by Cyclin-dependent Kinase (CDK)
pRBdoes1
Cell Cycle Control by Onco-Proteins
Figure 5-5, McKinnell, p. 148
Blocking pRB Function
Complete Deletion of Both Copies of RB1 Gene in
Transformed Cell Lineage
• Two Events in a Normal Somatic Cell
• One Event in Dominantly-Inherited RB1 Gene
Loss in Germ Line
Point Mutations
• Affecting E2F Binding Sites
• Affecting Phosphorylation Sites
Blocking of E2F Binding Site by Viral Oncoproteins
• SV40 Large T-Antigen
• E1A Adenovirus Oncoprotein
• E7 Papilloma Virus Oncoprotein
pRBBlock
Figure 8.21a The Biology of Cancer (© Garland Science 2007)
p. 276
RB Deletions and Mutations:
Germ-line vs Somatic
Germ-Line First Hit RB Deletions
• Familial, Bilateral Retinoblastoma
• Osteogenic Sarcoma
• Why These lineages and not all other cell types?
• Alternative Pathways (Redundancy) in Cell Cycle
Regulation?
Somatic Point Mutations or Deletions: Two Hits per Cell
• Bladder Cancers (33% associated)
• Small Cell Lung Cancer (SCLC): (60% Associated)
• Breast Cancers (33% Associated)
• Prostatic, Cervical Cancers, Some Leukemias
•
Sporadic Association
RBCxs
Restoring pRB Function
RB- Cell From Retinoblastoma, Osteogeneic
Sarcoma, Bladder Carcinoma, or Prostate Cancer
Insert Normal Rb1Gene by Microcell Transfer
Restoration of Normal Phenotype:
• Morphological Reversion to Normal
• Normal Growth Rate
• Loss of Growth in Soft Agar
• Loss of Tumorigenicity in Nude Mice
RBReturn
p53 Tumor Suppressor Protein
53 Kd Protein Attached to SV40 Large TAg
Transformed and Immortalized Transfected Cells
Found in many human and murine tumors and
neoplastic cell lines
All were mutant variants of a tumor suppressor
protein.
Germ-line Mutations in Li-Fraumeni sydrome
affecting one p53 Gene allele: Predispose to early
onset osteogenic sarcoma, adrenocortical
carcinomas, breast carcinomas, or brain cancers
p53Found
Normal Role of p53 Protein
• Localize in Nucleus.
• Transcription Factor Controlling Cell- replication
associated genes
• Anti-proliferative and Anti-neoplastic:
Prevents cells with damaged DNA from
entering the cell cycle
• Promotes Apoptosis in Cells with DNA Irreparably
Damaged
• Can bind to and down-regulate the bcl-2
apoptosis-blocking gene product
p53Role
Mutant or Deleted p53 in Clinical Human
Cancers
50 to 60% of Human Cancers Show Mutations,
Deletions, or Abberant Expression
Involving p53
Almost every histogenetic type:
bladder, bone, brain, breast
cervix, colon, esophagus, hematopoietic
larynx, liver, lung, lymphoid tissue,
malignant melanoma
ovary, pancreas, prostate, skin, stomach
thyroid, uterine endometrium
p53 Expression can be used prognostically
p53inCxs
Oncogenes Compared to Suppressor Genes
(from Ruddon, 3rd Ed., Table 8-3, p.320)
Oncogenes
One Mutational Event
Dominant Gain of Function
Not in Germ Line
Somatic Mutations: Yes
Activate Cell Growth
Gene Transfection: Can
Transform NIH3T3 Cells
Genetic Alterations:
Gene Rearrangements
Point Mutations
Gene Amplification
Suppressors
Two Mutational Events
Recessive Loss of Function
Heritable in Germ Line
Somatic Mutations: Yes
Inhibit Cell Growth
Gene Transfection: Suppress
Malignant Phenotype
Genetic Alterations:
Deletions
Point Mutations
OncvStop