Chapt. 18 Cancer

Molecular Biology of CancerStudent Learning Outcomes:• Describe cancer – diseases in which cells no longer respond• Describe how cancers come from genomic

mutations (inherited or somatic)

• Explain how some gain of function mutations in proto-oncogenes cause oncogenes

• Growth factors, receptors, Ras, cyclins• Explain how loss of function of tumor-

suppressor genes leads to cancer• P53, Rb, regulators of Ras

Karyotype analysis can reveal translocation

Karyotype analysis reveals transloction of chromosome 22 to 9 in CML

• chronic myelogenous leukemia has fusion protein Bcr-Abl

Fig. 18.1

Cancers involve sequential mutations

Fig. 18.1

Cancer involves sequential accumulation of mutations in genes involved in normal cell growth and differentiation:

• cancer cells do not respond to normal constraints

• cancer cells are immortal• increasing abnormalities, lack attachment

• Can inherit one bad gene

Damage to DNA can lead to mutaitons

Fig. 18.2 nitrosoamine causes GC -> AT mutations

A. Chemical and physical agents can damage DNA:

• Break DNA chains• Cause translocations• Modify bases • DNA damage can be repaired; mutations if not repaired• Carcinogens are mutagens• (see chapter 13)

B. Gain-of-function mutations in Proto-ongogenes

Fig. 18.3

Proto-oncogenes have normal roles for cell growth, proliferation: Mutate to Oncogenes

• Mutate so function better.in absence of normalactivating signals:

• Overexpress• Hyperactive protein• Fusion protein• Controlled by other promoter (inappropriate)

Mutations in DNA repair enzymes can cause cancer:

Mutations in DNA repair enzymes can cause cancer:

• DNA repair enzymes can correct damage

• They are tumor-suppressor genes (need to mutate both)

• Breast cancer linked to Brca1, Brca2 mutations• Xeroderma pigmentosum to excision repair

• HNPCC (hereditary nonpolyposis colorectal cancer) linked to mutations in mismatch repair enzymes

Table 1 examples of oncogenes

Classes of oncogenes gene mechanismGrowth factor

platelet-derived growth factor sis overexpressionGrowth factor receptor

platelet-derived gf receptor PDGFR translocationSignal transduction

G-proteins Ras point mutation tyr kinase abl translocation

Hormone receptors retinoid receptor RARa translocation

Transcription factors Myc amplificationCell-cycle regulators

cyclins cyclin D amplificationcyclin-dependent kinase CDK4 point mutation

Oncogenes and signal transduction pathways

Growth factor signaling pathways provide sites for proto-oncogene transforming mutations:

• Only need to mutate one allele (one gene)

Dominant effect

• See Table 1

Fig. 18.4

Signal transduction proteins and phosphorylation cascade

Fig. 18.5Phosphorylation cascade from activated Ras (Ras-GTP)

• Ras activates ser/thr kinase Raf• Raf is a MAPKKK

(mitogen-activated protein Kinase kinase kinase)

• Raf activates MEK• (a MAPKK)

• MEK activates MAP kinase• MAP kinase phosphorylates many

proteins • Transcription factors can mutate to

oncogenes• Mutations that keep proteins active

cause cell proliferation

Oncogenes and the Cell cycle

Fig. 18.6

Cyclins and cyclin-dependent kinases (CDK) control passage through cell cycle:

• Different cyclins and CDKs control different points• Cyclins transient; cdks persist

• Go is quiescent cell

• G1 -> S transition is critical• Commits to replication• Responds to hormones

• G2 -> M spindle check

Cyclin-CDK

Cyclins are synthesized, function to bind CDK, and degraded

CKIs are cyclin-dependent kinase inhibitors

CDKs are also regulated:• activated by PO4 (by CAK cyclin-

activating kinases)• inhibited by additional PO4

Oncogenes include:• Overactive cyclins, mutant cdks

Fig. 18.7

Control of G1/S transition in cell cycle:

Fig. 18.8

Control of G1/S is critical:regulation of E2F by Rb, CDK, cyclin CKI include p21, p16 (INK)

IV. Tumor-suppressor genes

Tumor-suppressor genes encode proteins that inhibit cell proliferation: mutate both copies

Table 18.2 class protein locationAdhesion protein E-cadherin cell surface

Signal transduction NF-1 under membrane

Transcription factorcell-cycle regulator p16 (INK4) nucleus

Rb nucleus

Cell cycle/ apoptosis p53 nucleus

DNA repair BRCA1 nucleus

A. Some tumor suppressors regulate cell cycle directly

Retinoblastoma (Rb) protein binds E2F, prevents transcription and G1/S until signal:(Fig. 18.8)

• Mutate both copies

• Cell loses control

• Hereditary cancer tendency

Fig. 18.9

Phosphorylation controls transition G1 to S: cycD-Cdk inactivates Rb ->E2F activates transcription

Genetics 15.12A

Phosphorylation controls transition G1 to S:E2F activated transcription:cyclins A, E and Cdk2 activate prereplication complexes

Genetics Fig 15.12 B

P53 is guardian of genome

P53 responds to DNA damage: stops cell cycle to permit repair (or cell suicide – apoptosis)

• P53 mutated in 50% of tumors• Induction of p21 stops cyclin-CDK• Induction of GADD stops replicaiton, permits repair

Fig. 18.10

Some tumor suppressors affect receptors, signal transduction

Fig. 18.11

1. Regulators of Ras are tumor suppressors:

• GAP proteins (GTPase) bind active Ras, stop signal

• NF-1 (neurofibromin) is GAP for RAS in neuronal tissue

• Mutated NF-1 give neurofibromatosis

2. Tumor suppressors and proto-oncogenes

Tumor suppressors and proto-oncogenes in path:

• Patched inhibits Smoothened, coreceptor

• HH ligand binding releases inhibition, activating signal

• S is proto-oncogene; mutation can keep active

• P is tumor suppressor; mutations ruining keep S active Fig. 18.12

Tumor suppressor genes can affect cell adhesion

Tumor cells metastasize, lose cell adhesion:• Normal adhesion from cadherins, link cytoskeleton• Mutated cadherins promote cell migration

-catenin also transcription factor;• Bound by inhibitor APC• APC is tumor suppressor

Fig. 18.13

Cancer involves sequential mutations

Cancer involves sequential mutations that increase aberrant cell activity:

2-hit model: mutations in at least two different types of genes

(tumor suppressor, oncogene)

(also lack of apoptosis)

Fig. 18.18

Cancer is many different diseases

Fig. 18.19

Cancer is many different diseases at the molecular level:• not all colon cancers have same defect• defects in particular signaling pathways can cause cancers in different tissues

Viruses can also cause cancer

RNA retroviruses:HTLV-1 adult T cell luekemia

HIV immunosuppressionnon-Hodgkins lymphoma

Hepatitis C liver

DNA viruses:HPV: cervical cancer

Epstein Barr (a herpesvirus) – interfere apoptosis

Review questions

2. The mechanism through which Ras becomes an oncogenic protein is which of the following?

A.Ras remains bound to GAP

B.Ras can no longer bind cAMP

C.Ras has lost its GTPase activity

D.Ras can no longer bind GTP

E.Ras can no longer be phosphorylated by MAP kinase