BCH 475 Biochemistry of Carcinogenesis Professor A. S. Alhomida

BCH 475 Biochemistry of Carcinogenesis Professor A. S. Alhomida
King Saud University College of Science Department of Biochemistry Disclaimer The texts, tables and images contained in this course presentation are not my own, they can be found on: References supplied Atlases or The web sites BCH 475 Biochemistry of Carcinogenesis Professor A. S. Alhomida Summer, 2008 Part 2

Oncogenesis

Oncogenesis Arises from
Spontaneous gene or chromosome mutations Exposure to mutagens or radiation Activity of genes introduced by tumor viruses Some cancers are inherited (individuals may be predisposed)

Classes of Cancer Genes

Three classes of genes are mutated in cancer: (1) Proto-oncogenes whose products stimulate cell proliferation Cab be mutated into oncogene that induce cell transformation (cancer cells)

Proto-oncogenes Proto-oncgenes Oncogenes
Are genes that possess normal gene products and stimulate normal cell development Oncogenes Arise from mutant proto-oncogenes Are more active than normal or active at inappropriate times and stimulate unregulated cell proliferation

(2) Tumor suppressor genes whose products normally inhibit proliferation, negative regulatory protein

(3) Mutator genes whose products ensure accurate replication and maintenance of the genome Types of genes which may mutate to cause cancer (mutators) DNA repair genes Telomerase

Oncogenic Viruses (Viral Oncogenes)

Oncogenic Viruses Oncogenic viruses or viral Carcinogenesis
Viruses which produce cancer There is no single mechanism by which viruses cause tumors

Viral Oncogenes Tumor viruses induce infected cells to proliferate and produce a tumor There are two types, based on the viral genome: RNA tumor viruses transform cells by introducing viral oncogenes An oncogene is any gene that stimulates unregulated proliferation

Viral Oncogenes RNA tumor viruses Possess viral oncogenes
Derived from cellular proto-oncogenes capable of transforming cells to a cancerous state

Viral Oncogenes (2) DNA tumor viruses
Another class of tumor viruses; do not carry oncogenes, but induce cancer by activity of viral gene products on the cell (no transformation per se)

Cell Cycle and Cancer

Cell Cycle and Cancer Cell differentiation occurs as cells proliferate to form tissues Cell differentiation correlates with loss of ability to proliferate; highly specialized cells are terminally differentiated

Cell Cycle and Cancer Terminally differentiated cells have a finite life span, and are replaced with new cells produced from stem cells Stem cells are capable of self-renewal; cells divide without undergoing terminal differentiation

Incidence of Cancer

Incidence of Cancer (1) Sporadic cancers
The more frequent type, do not appear to have an hereditary cause

Incidence of Cancer (2) Familial (hereditary) cancers Run in families
Retinoblastoma Is the most common eye tumor in children birth to 4 years Early treatment (usually gamma radiation) is over 90% effective

Two-hit Mutation Model for Cancer

Two-hit Mutation Model
Cancers can be caused by viruses, but most result from mutations in cellular genes Usually these mutations have accumulated over time, and research has identified the genes involved

Retroviruses and Oncogenes

Single-stranded RNA virus that replicates via double-stranded DNA intermediate RNA is converted to cDNA by reverse transcriptase DNA integrates into host chromosome and is transcribed

Retroviruses Genes Three types of genes occur in most retroviruses:
Gag (group antigen) Codes the protein core Pol (polymerase) Codes reverse transcriptase and an enzyme for proviral integration Env (envelope) Codes envelope glycoproteins

Oncogenic retroviruses (v-onc) transform the cell and cause cancer (also called transducing viruses) Different retroviruses carry different oncogenes responsible for different types of cancer e.g. v-src in RSV

Most oncogenic retroviruses (but not RSV) are defective and do not possess a full set of virus life-cycle genes Transform cells but do not produce progeny viruses

Defective retroviruses produce progeny with the help of a normal virus that co-infects cell and supplies missing gene products Helper virus supplies missing gene products → viral expression

Transducing Retroviruses
Retroviruses that carry an oncogene (v-onc) are transducing retroviruses Different types of cancer are caused by different v-onc genes (e.g., the sarcoma gene, v-src, of RSV) RSV-infected cells rapidly transform, Produce progeny RSV particles Because RSV is unusual in having intact gag, pol, and env genes

Transducing Retroviruses
All other transducing retroviruses are defective, lacking one or more genes needed to replicate If a helper virus supplies the missing gene product(s) progeny can be made

Structures of Four Defective Transducing Viruses

RNA Tumor Viruses They are all retroviruses, and their oncogenes are altered forms of normal host genes Examples include: Rous sarcoma virus Feline leukemia virus Mouse mammary tumor virus Human immunodeficiency virus (HIV-1, cause of AIDS)

RNA Tumor Viruses Structurally, retroviruses have:
Two copies of the 7-10 kb ssRNA genome A protein core (often icosahedral) An envelope derived from host membrane and bearing viral glycoproteins used to enter a host cell

RNA Tumor Viruses The retroviral life cycle was first characterized (1910) for a “filterable agent” from a chicken tumor, later named the Rous sarcoma virus (RSV) RSV’s genome organization is known

RNA Tumor Viruses

Mechanism of RSV Action

Upon retroviral infection, the ssRNA genome is released from the virus particle, and reverse transcribed to dsDNA (proviral DNA) by reverse transcriptase carried in the virus particle

Proviral DNA integrates into host chromosome: The 5’ (left) end of the viral genome has sequences R and U5, while the 3’ (right) end has sequences U3 and R During proviral synthesis, genome ends are duplicated to produce long repeats (LTR) of U3-R-U5 The LTRs contain transcription regulatory signals for viral genes

Proviral DNA is ligated to produce a circular dsDNA with two adjacent LTRs Staggered nicks in proviral and host DNA are used for integration of the viral genome into the host chromosome Single-stranded gaps are filled, producing short, direct repeats in host DNA flanking the provirus

Host RNA polymerase II transcribes the proviral DNA, and viral mRNAs are produced by alternative splicing Three genes are characteristic of retroviruses: The gag (group antigen) gene encodes a precursor protein that is cleaved to form the protein core (capsid)

The pol (polymerase) gene produces a precursor protein cleaved to make reverse transcriptase and an enzyme for proviral integration The env (envelope) gene encodes the envelope glycoprotein, used to infect a host cell

Features of LTRs

Oncogenic Retroviruses Not Involved in the Cell Cycle

Oncogenic retroviruses carry an oncogene that is not involved in the cell cycle Different retroviruses carry different oncogenes In RSV the oncogene is src

Most retroviruses cannot replicate due to missing life-cycle genes (RSV is an exception) Retroviruses without oncogenes (nononcogenic retroviruses) direct their own life cycle, and do not change the growth properties of infected cells

Nononcogenic Retroviruses

Life Cycle of Nononcogenic Retrovirus

They include HIV-1, a virus that causes AIDS, rather than cancer The bullet-shaped capsid is surrounded by an envelope containing viral gp120 glycoproteins The genome contains gag, pol and env genes, and several other genes used for gene regulation (e.g., tat regulates gag and pol expression)

Infection begins when the gp120 glycoprotein in the HIV-1 envelope binds: Most commonly, the CD4 receptor of a helper T cell A different receptor on a different type of cell (e.g., macrophage, glial cell in brain, regulatory cell of intestinal lining)

Mechanism of Nononcogenic Retroviruses

Mechanism of Nononcogenic Retroviruses
The virus particle enters the cell, the protein capsid is lost and the viral life cycle begins Normal viral replication causes death of cells infected with HIV-1, depleting the helper T cells needed to mount an immune response Unable to combat infection, AIDS patients frequently die of infections and cancers

Cellular Proto-oncogenes

Mid-1970s: J. Michael Bishop & Harold Varmus (Nobel Prize 1989) Demonstrated normal animal cells contain non-cancer causing genes closely related to viral oncogenes

Early-1980s: R. A. Weinberg & M. Wigler demonstrated a variety of human tumor cells contain oncogenes, which transform normal cells growing in culture to cancer cells

Most human and animal oncogenes are mutated forms of normal cellular genes (proto-oncogene = normal state)

v-onc Viral oncogene, carried by a virus c-onc Cellular oncogene, resides in host chromosome

Chicken c-src Proto-oncogene and v-src Oncogene

Genomic Changes that Cause Proto-oncogene Activation
Genomic changes (amplification, insertion & translocation) that cause proto-oncogene activation: Amplification c-myc, c-abl, c-myb, c-erbB, c-K-ras, mdm-2 Presence of known oncogenes in amplified region Amplification of same oncogenes in many cancers

Insertion Insertion of retrovirus LTR over-expresses c-myc Insertion of ALV activates c-myc gene Translocation Reciprocal translocation by illegitimate recombination Immunoglobulin or TCR gene and c-myc oncogene

Increased c-myc expression after translocation c-myc coding sequences are unaltered in all cases

Evidence of oncogenic potential of c-myc gene: Transgenic mice carrying c-myc that: Linked to B lymphocyte enhancer → lymphoma Under mouse mammary tumor virus LTR → various cancers

Translocation can generate hybrid oncogenes and human cancers CML & Philadelphia chromosome c-abl gene on chromosome 9 and bcr gene on chromosome 22 Why is the hybrid bcr-abl protein oncogenic? Activation of ras pathway for transformation

Mechanism of Retroviruses Oncogenesis

Retrovirus integrates into host chromosome near a cellular proto-oncogene by random recombination Deletion fuses retrovirus transcription signal sequences with proto-oncogene sequences

In the process, parts of the viral DNA sequences typically are deleted (this is how the defective oncogene is created) Viral “progeny” carry the cellular gene, but now under the influence of viral promoters

Most transducing viral oncogenes are defective and cannot replicate independently

If mRNA is packaged into a virus particle along with a normal virus genome (co-infection), reverse transcriptase produces a new defective oncogene by switching templates during cDNA synthesis

Template switching + lack of proofreading during DNA replication result in rapid evolution of oncogenic retroviruses

Formation of Transducing Retrovirus Oncogene

DNA Tumor Viruses

DNA Tumor Viruses Do not carry oncogenes
Transform cells to the cancerous state through actions of genes in the viral genome

DNA Tumor Viruses Examples include viruses in the following groups:
Papovaviruses (warts and human cervical cancer) Hepatitis B Herpes Adenoviruses Pox viruses

DNA Tumor Viruses DNA viruses induce production of cellular DNA replication enzymes, which are used in viral replication Rarely, viral DNA integrates into the host genome instead, and may produce protein(s) that stimulate the cell to proliferate

DNA Tumor Viruses An example:
The papovavirus group includes many different papillomaviruses, some of which cause: Human warts Human cervical cancer (HPV-16, HPV-18), due to action of the E6 and E7 genes, which influence cell growth and division

Proto-oncogenes

Oncogenes Oncogene is mutated form of normal genes called proto-oncogene Control of cell proliferation and differentiation

Oncogenes Oncogenic virus Oncogenic DNA virus Oncogenic RNA virus
Viruses are named because of reverse transcriptase Retrovial oncogene, src

Proto-oncogen Activation
Normal cell genes from which oncogene originated, encoding proteins that function in: Signal transduction pathway Controlling normal cell proliferation

Proto-oncogen Activation

Functions of Oncogene Products
Uncotrolled proliferation of cancer cell Defective differentiation Failure to programmed cell death

ras Proto-oncogenes Involved in signal transduction pathway as are many proto-oncogene products ras family genes mutated in 40% of all cancers

ras Proto-oncogenes Involved in signal transduction pathway from growth factor receptor to nucleus G protein Mutant form lacks GTPase activity and remains active

Proto-oncogene and Oncogene Protein Products
~100 different oncogenes have been identified To understand the cancer Understand the function of protein products coded by the proto-oncogenes

Protein Products of Proto-oncogenes
Proto-oncogenes fall into classes with characteristic protein products, all of which stimulate cell growth Examples:

Examples of Protein Products of Proto-oncogenes
An example of growth factors is the viral oncogene v-sis, which encodes platelet-derived growth factor (PDGF) Deriving from mammalian blood platelets, PDGF causes fibroblasts to grow as part of wound-healing Introduction of a cloned PDGF gene into cells that normally do not express it (e.g., fibroblasts) transformed the cells

Inappropriately expressed growth factors, therefore, can cause cancer An example of protein kinases is the src gene product, which encodes pp60src, a nonreceptor protein kinase Both cellular and viral versions of the pp60src protein phosphorylate tyrosine (rather than serine or threonine

Protein kinases are known to be involved in many aspects of cell signaling and growth regulation

All known proto-oncogenes are involved in positive control of cell growth and division

Two classes: Growth factors Regulatory genes involved in the control of cell multiplication Protein kinases Add phosphate groups to target proteins, important in signal transduction pathways

Mechanism of Conversion of Proto-oncogenes to Oncogenes

Conversion of proto-oncogenes to oncogenes relaxes cell control, allowing unregulated proliferation Examples: Point mutations in the coding or controlling sequences can either change the gene product or alter its expression

The ras genes are an example: A point mutation produces a mutant protein that can cause cancer in many different types of cells G proteins lose regulation, and constitutive growth signals are transmitted to the cell

Deletions of coding or controlling sequences can change the amount of activity of growth stimulatory proteins, allowing proliferation. The myc gene is an example: The myc gene product is a transcription factor that activates genes involved in cell division

Deletions can remove upstream sequences, allowing expression from an alternative promoter and changing the amount or activity of the protein product Gene amplification, caused by random overreplication of regions of genomic DNA, has been found in tumor cells Multiple copies of ras in mouse adrenocortical tumors are an example

Point mutations that result in constitutively active protein products Localized gene amplification of a proto-oncogene leading to over-expression

Chromosomal translocation that brings a growth-regulatory gene under control of a different promoter that causes inappropriate expression Note: These are generally gain-of-function mutations

Gain-of-function Mutations Convert Proto-oncogenes into Oncogenes

Gain-of-function Mutations
Oncogenes were first identified in cancer-causing retroviruses The Rous sarcoma virus (RSV) contains a gene (src) that is required for cancer-induction but is not required for viral function Normal cells contain a related gene that codes for a protein-tyrosine kinase

Gain-of-function Mutations
The normal gene (c-src) is the proto-oncogene, while the viral gene (v-src) is an oncogene that codes for a constitutively active mutant protein-tyrosine kinase Many DNA viruses also contain oncogenes but these have integral functions in viral replication

Slow-acting Carcinogenic Retroviruses can Activate Cellular Proto-oncogenes

Retroviruses Activate Cellular proto-oncogenes

Tumor Suppressor Genes

Harris (1960s) showed that fusion of cancer cells and normal cells did not always result in a tumor, indicating the existence of tumor suppressor genes

In certain cancers, both homologous chromosomes show deletion of specific regions, the sites of tumor suppressor genes that inhibit cell growth and division

Human examples include: Breast cancer Colon cancer Lung cancer Action of tumor suppressors is the opposite of proto-oncogenes

Both tumor suppressor genes must be lost for unregulated growth to occur (they are recessive), while only one mutation is needed to change a proto-oncogene to an oncogene (it is dominant)

The gene’s normal function is to regulate cell division Both alleles need to be mutated or removed in order to lose the gene activity The first mutation may be inherited or somatic

The second mutation will often be a gross event leading to loss of heterozygosity in the surrounding area Block abnormal growth and malignant transformation

Proto-oncogene; dominant in action Tumor-suppressor gene; recessive in action Examples: Rb, p53, INK4, APC, DCC

Functions of tumor suppressor gene products Tumor development by eliminating negative regulatory proteins Examples: WT1, Rb and INK4, p53 gene product, APC and DCC

Five Proteins are Encoded by Tumor-Suppressor Genes
Intracellular proteins that regulate or inhibit progression through a specific stage of the cell cycle Receptors for secreted hormones that inhibit cell proliferation Checkpoint-control proteins that arrest the cell cycle

Five Proteins are Encoded by Tumor-Suppressor Genes
Proteins that promote apoptosis Enzymes that participate in DNA repair Note: These are usually loss-of-function mutations

Loss-of-function Mutations in Tumor-suppressor Genes
The first tumor-suppressor gene was identified in patients with inherited retinoblastoma

Loss-of-function Mutations in Tumor-suppressor Genes

Loss of Heterozygosity of Tumor-Suppressor Genes Occurs by Chromosome Mis-segregation or Mitotic Recombination

Comparison of the Effects of Tumor Suppressor gene and Proto-oncogene
Comparison of the Effects of Tumor Suppressor gene and Proto-oncogene Mutations

Lectures 28 and 29, Slides Proto-oncogenes and tumor-suppressor genes: the seven types of proteins that participate in controlling cell growth

p53 Tumor Suppressor Gene
Mutated (inactivated) in more than 50% of all cancers p53 regulates (activates or represses) transcription of more than 50 different genes

Mutations in p53 Abolish G1 checkpoint Control
Some human carcinogens cause inactivating mutations in the p53 gene and p53 activity is also inhibited by certain proteins encoded by DNA tumor viruses

Mutations in p53 Abolish G1 checkpoint Control
Lectures 28 and 29, Slides Mutations in p53 Abolish G1 checkpoint Control

Mutations in the p53 gene occur in more than 50% of human cancers Because p53 is a tetramer, a point mutation in a single allele can inhibit all p53 activity

MDM2, a protein that normally inhibits the ability of p53 to halt the cell cycle, is overexpressed in certain cancers One human papillomavirus protein, E6, binds to and inhibits p53

The large T protein from the DNA monkey papovavirus binds to both p53 and Rb, inhibiting their function. Carcinogens such as benzo(a)pyrene and aflotoxin induce inactivating mutations in p53

p53 regulated by Mdm2 (prevents the phosphorylations and acetylations that activate inactive p53) Activated p53 levels rise rapidly if DNA is damaged or repair intermediates accumulate

p53 Tumor Suppressor Genes
Mutations in p53 are implicated in ~50% of human cancers, including cancers of the: breast, brain, liver, lung, colorectal, bladder, and blood Development of tumors requires mutations on two p53 alleles

Codes a 393 amino acid protein involved in transcription, cell cycle control, DNA repair, and apoptosis (programmed cell death) p53 binds to several genes, including WAF1, and interacts with at least 17 cellular and viral proteins

Transgenic mice with deletions of both p53 alleles are viable, but 100% develop cancer by ten months of age Effects of DNA damage and normal (non-mutant) p53 lead to cell growth arrest

p53 Function Suppresses progression through the cell cycle in response to DNA damage Initiates apoptosis if the damage to the cell is severe acts as a tumor suppressor It is a transcription factor and once activate

p53 Function It represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control

p53 Function Activated p53 acts as transcription factor to turn on genes that Arrest the cell cycle so DNA can be repaired Initiates synthesis of p21, which inhibits CDK4/cyuclinD1 complex, blocking entry into S phase Genes expressed which retard rate of DNA replication Other products block G2/M progression

p53 Function Initiate apoptosis if DNA cannot be readily repaired
Turns on Bax gene, represses Bcl2 gene Bax homodimers activate process of cell destruction Cancer cells lacking p53 do not initiate pathway even if DNA/cellular damage is great

pRB Function Tumor suppressor protein that controls the G1/S checkpoint Found in nucleus and activity regulated by level of phosphorylation (by CDK4/cyclinD1 complex)

pRB Function Nonphosphorylated version binds to TFs such as E2F, inactivating them Free E2F and the other regulators turn on >30 genes required for transition to S phase

Role of pRB in Regulating Cell Division

Mechanism of Tumor Suppressor Genes

Oncogenic virus enters the cell DNA of virus enters cells chromosome If retrovirus, first, the RNA is converted to DNA (provirus) The provirus DNA enters the cell

Virus has cancer causing gene = oncogene transformation: Cell becomes cancer cell In 1976 (Varmus and Bishop from UCSF received Nobel Prize 1989) Oncogenes found in normal cells (Same nucleotide sequence or genetic recipe) called protooncogene

Most oncogenes are dominant genes Whole lists of oncogenes now discovered for animal and a few for humans We all have protooncogenes: Human’s total genome is 100,000 genes probably < 100 are protooncogenes

40 discovered so far (50 Talaro) They have normal functions that are important Now we know that all cancers are the result of an oncogene

RB1 Tumor Suppressor Gene
Retinoblastoma 1 gene Involved in breast, bone, lung, bladder and retinal cancers (among others)

RB1 Tumor Suppressor Gene
Inheriting one mutated (inactivated) copy of gene increases chances of retinoblastoma formation from 1/14,000-20,000 to 85% (plus increases other cancer rates) Loss of second copy in a cell eliminates function Normal cells unlikely to lose both good copies

DNA Repair Genes (Mutator Genes)

Third category of cancer-causing genes Excision, mismatch repair Cancer effects are indirect Defective DNA repair = increase rate of failure to repair mutations Mutations accumulate in the genome

Significance Have an increased chance of mutation in a proto-oncogene and/or tumor suppressing gene

Mutator Genes

Mutator Genes Mutator gene increases spontaneous mutation rate of other genes Mutator gene products are involved in DNA replication and repair; mutations make the cell error prone HNPCC-OMIM , human non-polyposis colon cancer

Mutator Genes Mutation at any one of two genes (hMSH2, hMLH1, hPMS1, hPMS2) leads to predisposition Tumor formation requires mutation at the second allele All four genes have homologs in yeast DNA blood tests are available for all four genes

Lectures 28 and 29, Slides Defects in DNA-repair Systems Perpetuate Mutations and are Associated with Certain Cancers

Virus-encoded Activators of Growth-factor Receptors Act as Oncoproteins

Activating Mutations or Overexpression of Growth-factor Receptors can Transform Cells

Constitutively Active Signal-Transduction Proteins are Encoded by Many Oncogenes

Chromosomal Abnormalities are Common in Human Tumors
In Burkitt’s lymphoma c-myc is translocated to chromosome near an antibody-gene enhancer

A translocation between chromosomes 9 and 22 causes the formation of the chimeric bcr-abl oncogene found in virtually all patients with chronic myelogenous leukemia

Passage from G1 to S Phase is Controlled by Proto-oncogenes and Tumor-suppressor Genes

Loss of TGF Signaling Contributes to Abnormal Cell Proliferation and malignancy

Finding Tumor Suppressor Genes
Recessive genes, like those for tumor suppression, are more difficult to detect than dominant genes Positional cloning, the search for DNA variations between normal and tumor cells, was finally successful in isolating several tumor suppressor genes

Retinoblastoma

Retinoblastoma Retinoblastoma has two forms:
Sporadic retinoblastoma (60%) develops in children with no family history of retinoblastoma, and occurs in one eye (unilateral tumor)

Retinoblastoma Hereditary retinoblastoma (40%) patients typically develop multiple tumors involving both eyes (bilateral tumors) Onset is usually earlier in the hereditary form Siblings and offspring often develop the same type of tumor Pedigrees of affected families are consistent with a single gene responsible for retinoblastoma

Knudson’s Two-hit Mutation Model for Retinoblastoma

Knudson’s Model for Retinoblastoma
Two mutations are required for the development of retinoblastoma Sporadic retinoblastoma Child starts with two wild type alleles (RB+/RB+) Both alleles must mutate to produce the disease (RB/RB)

Probability of both mutations occurring in the same cell is low; only one tumor forms (e.g., one eye)

Hereditary retinoblastoma Child starts with heterozygous alleles (RB/RB+) Only one mutation is required to produce disease (RB/RB) Mutations resulting in loss of heterozygosity (LOH) are more probable in rapidly dividing cells, and multiple tumors occur (e.g., both eyes)

Retinoblastoma alleles are recessive; only homozygotes (RB/RB) develop tumors Retinoblastoma appears as dominant in pedigree analysis: RB/RB+ individuals are predisposed and have a significant incidence of the disease

Homozygous dominant individuals (RB+/RB+) require two mutations in the same cell to develop the cancer Retinoblastoma was mapped to the long arm of chromosome 13 (13q14.1-q14.2)

Mutations occur in a gene that encodes a growth inhibitory factors (tumor suppressor gene) Retinoblastoma is rare among cancers; most cancers result from a series of mutations in many different genes

Retinoblastoma

The Retinoblastoma Tumor Suppressor Gene
The human RB tumor suppressor gene has been mapped (13q14.1-q14.2) and sequenced Its 180 kb of DNA encodes a 4.7 kb mRNA that produces a 928-amino-acid nuclear phosphoprotein, pRB pRB is expressed in every tissue type examined, regulating cell cycle and all major cellular processes

Tumor cells have point mutations or deletions in the gene, leading to loss of pRB function

Karyotype analysis detects about 5% of RB mutants, and the remainder are difficult to detect even with molecular techniques Mitotic recombination Chromosomal nondisjunction Gene conversion

The cell cycle transition from G1 to S is regulated by pRB, committing the cell to the rest of the cycle In a normal G1 cell, pRB binds two transcription factors, E2F and DP1 As long as pRB stays bound to the factors, the cell remains in G1 or enters G0

At the signal to progress through the cell cycle, cyclin/cyclin-dependent kinase (Cdk) phosphorylates pRB so that it is unable to bind E2F Free E2F now binds and activates transcription of genes required for entry into S phase After the cell completes mitosis, pRB is dephosphorylated

In a cell with two mutant RB alleles: If pRB is present, it is unable to bind E2F/DP1 Target genes are activated, and the cell enters S phase

Several viruses (e.g., adenovirus, SV40) make proteins that complex with pRB, blocking its ability to bind E2F, and so allowing the S phase genes to be activated

pRB bind other cellular proteins, including those involved with all three RNA polymerases: A component of the RNA polymerase II basal transcription machinery Factors for rRNA synthesis by RNA polymerase I Factors for tRNA synthesis by RNA polymerase III

Retinoblastoma indicates that pRB may also play a role in regulating development, perhaps by causing cells to become terminally differentiated

Retinoblastoma Tumor Suppressor Genes
Mapped to gene chromosome 13 and sequenced. 180 kb; codes a 4.7 kb mRNA that produces a 928 amino acid nuclear phosphoprotein, pRB pRB is expressed in every tissue that has been examined and regulates the cell cycle

Retinoblastoma Tumor Suppressor Genes
Retioblastoma tumor cells possess point mutations or deletions, which render pRB defective In hereditary retinoblastoma, second RB mutation often is identical to the inherited one (a possible example of gene conversion)

Effects of DNA Damage and Normal p53

Breast Cancer Tumor Suppressor Genes
Breast cancer affects 1 in 10 women and represents 31% of cancers in women (~185,000 women diagnosed each year)

~ 5% of breast cancers are hereditary; age of onset for hereditary breast cancer is earlier than other forms (mutations at two alleles) Many genes involved; BRCA1 and BRCA2 are thought to be tumor suppressor genes

BRCA1 is important for homologous recombination, cellular repair of DNA damage, and transcription of mRNA Mutations in BRCA1 also are involved in ovarian cancer BRCA2 plays a role in timing of mitosis in the cell cycle

Multi-step Nature of Cancer
Cancer is a stepwise process, typically requiring accumulation of mutations in a number of genes ~6-7 independent mutations typically occur over several decades:

Multi-step Nature of Cancer
Cancer is a stepwise process, typically requiring accumulation of mutations in a number of genes ~ 6-7 independent mutations typically occur over several decades: Conversion of proto-oncogenes to oncogenes Inactivation of tumor suppressor genes

Bert Vogelstein’s model of colorectal cancer
OMIM

How does HPV cause cancer?
Gene products of certain sub-type (eg 16 and 18) interfere with normal cellular proteins Early viral proteins E6 and E7 bind p53 and RB proteins respectively

How does HPV cause cancer?

BCH 475 Biochemistry of Carcinogenesis Professor A. S. Alhomida

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