tumor suppressor genes folder title: suppress updated: april 5, 2007 ttloffgn

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 InstabilityProgressive Random Genetic InstabilityPoint Mutations and Failure to Repair DNATranslocations 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 GenesAdditions• Aberrant Chromosome Replication: Trisomy & Aneuploidy• Amplifications and Repeats

GoWrong

Specific Genetic Abnormalities Associated with Specific Cancers

Chronic Myelogenous Leukemia

Burkitt's Lymphoma

Myelodysplasia and AcuteMyelogenous Leukemia

Meningioma

Reciprocal Translocation, 9&22

Reciprocal Translocation, 8&14

Trisomy 8

Monosomy 22

SpecCx

Chromosomal Deletions Associated with Specific Neoplasms1p Melanoma, Neuroblastoma,

Thyroid Cx, Ductal Breast CxMultiple Endocrine Neoplasia

1q Breast Carcinoma3p Small-cell Lung Cx, Renal Cell Cx,

Cervical Cx5q Familial Polyposis Coli, Colorectal Cx11q Wilm's Kidney Tumor, Breast Cx,

Rhabodmyosarcoma, Bladder Cx13q Retinoblastoma, Osteogenic Sarcoma

Small-cell Ling Cx, Ductal Breast Cx17p Small-cell Lung Cx, Colorectal Cx,

Breast Cx, Osteosarcoma17q Neurofibroma18q Colorectal Cx22 Menigioma, Acoustic neuroma, Pheochromocytoma

GenLost1From: JNCI, 83:92 (1991)

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


• 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?

OncProb3

See Sidebar 7.5, p. 226 in Weinberg

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


• 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 NeoplasmsWhat's Missing?

1p Melanoma, Neuroblastoma, Thyroid Cx, Ductal Breast CxMultiple Endocrine Neoplasia

1q Breast Carcinoma3p Small-cell Lung Cx, Renal Cell Cx,

Cervical Cx5q APC* Familial Polyposis Coli, Colorectal Cx11q WT1 Wilm's Kidney Tumor, Breast Cx,

Rhabodmyosarcoma, Bladder Cx13q Rb1 Retinoblastoma, Osteogenic Sarcoma

Small-cell Ling Cx, Ductal Breast Cx17p p53 Small-cell Lung Cx, Colorectal Cx,

Breast Cx, Osteosarcoma17q NF1 Neurofibroma18q DCC Colorectal Cx22 Menigioma, Acoustic neuroma,

PheochromocytomaGenLost2From: JNCI, 83:92 (1991)

* Added 2003

Proposed Role for

APC Protein in Mitosis

APCMitosis

Figure 7.22 The Biology of Cancer (© Garland Science 2007) p. 226

Familial Adenomatous Polyposis Coli

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-ProteinsFigure 5-5, McKinnell, p. 148

Blocking pRB FunctionComplete 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 LinePoint Mutations• Affecting E2F Binding Sites• Affecting Phosphorylation SitesBlocking of E2F Binding Site by Viral Oncoproteins• SV40 Large T-Antigen• E1A Adenovirus Oncoprotein• E7 Papilloma Virus Oncoprotein

pRBBlock

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 FunctionRB- 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, breastcervix, colon, esophagus, hematopoieticlarynx, liver, lung, lymphoid tissue,malignant melanomaovary, pancreas, prostate, skin, stomachthyroid, uterine endometrium

p53 Expression can be used prognostically

p53inCxs

Oncogenes Compared to Suppressor Genes(from Ruddon, 3rd Ed., Table 8-3, p.320)

OncogenesOne Mutational EventDominant Gain of FunctionNot in Germ LineSomatic Mutations: YesActivate Cell GrowthGene Transfection: Can Transform NIH3T3 CellsGenetic Alterations: Gene Rearrangements Point Mutations Gene Amplification

SuppressorsTwo Mutational EventsRecessive Loss of FunctionHeritable in Germ LineSomatic Mutations: YesInhibit Cell GrowthGene Transfection: Suppress Malignant PhenotypeGenetic Alterations: Deletions Point Mutations

OncvStop

tumor suppressor genes folder title: suppress updated: april 5, 2007 ttloffgn

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