BioChem Cancer (12)

rare tumors that arise from neural precursor cells in the immature retina caused by missing Rb gene (chrom 13, tumor suppressor gene); only a small number of mutations are required to form retinoblastomas; disease can either be hereditary or not

proteolytic enzymes

• 1) tumor suppressors
• 2) proto-oncogenes

• Carcinomas arise from epithelial cells
• Sarcomas: connective tissues, muscle, cartilage, fat, or bone
• Leukemias and lymphomas: blood cells

• genes that encode proteins that help control cell growth and proliferation
• such proteins generally exert a REPRESSIVE effect on the cell cycle

p53, pRb, WT1, BRCA1, BRCA2, NF1, APC, PTEN

phosphoPROTEIN encoded by RB gene located in nucleus that in its UNphosphorylated state blocks progression through the cell cycle

True: loss of both alleles is necessary for tumor formation; this is true of most tumor suppressors, with the notable exception of p53

FALSE: RB is a tumor suppressor gene

• Mitosis/Cyclin B [Cdk 1]
• S/Cyclin A [Cdk 2]
• G1/S, E [Cdk 2]
• G1/Cyclin D [Cdk 4 or 6]

Cyclins D & E

E2F

It stimulates synthesis of proteins required for the S-phase of the cell cycle (eg. pol-alpha/primase)

• a phosphorylated, nuclear protein that has the ability to bind DNA and detects DNA damage; in response it can either cause:
• 1) G1/S arrest (via p21 transcription)
• 2) apoptosis
• *clinical correlate: sarcomas, carcinomas

regulatory regions found on genes that can be regulated by p53; also called enhancers

the fact that they don't undergo apoptosis

• gene target by p53 that when transcribed produces a protein that halts cell cycle in G1 phase by binding to Cdk/cyclin complexes
• this allows for DNA repair to take place
• *without p53 no p21 protein is made --> cell cycle progresses with damaged DNA*

a rare inherited cancer condition caused by germline mutations of the p53 gene

p21 gene, which codes for a protein that halts the cell cycle in the G1 phase

It binds to and inhibits the cyclin/Cdk-2 complex, preventing the cell from advancing through the G1/S checkpoint

True

• Gene          Tumor
• RB ---> Retinoblastoma
• p53 ---> Sarcomas, carcinomas
• NF1 ---> Neuroblastoma
• APC ---> Colon, stomach
• BRCA ---> Breast Cancer

genes that encode growth-promoting proteins (altered components of pathways that activate cell division in response to growth factor stimulation)

signal transduction: movement of signals from outside the cell to the nucleus

• mutated copies of proto-oncogenes (mutated copies of cellular genes linked with various cancers)
• usually DOMINANT

• type of tyrosine kinase receptor involved in signal transduction; has enzymatic activity
• when phosphorylated can start cascade

• 1) Excess growth factors (eg.
• 2) Defective growth factor receptors
• 3) Defective signaling molecules
• 4) Altered regulation of transcription factors

ONLY ONE

cell membrane (eg. PDGF & insulin receptors)

the sis oncogene - originally identified in a transforming retrovirus

• in the cytoplasm or nucleus
• upon ligand binding, they migrate to the nucleus where the complex affects gene transcription

It encodes a modified form of the EGF receptor that always produces intracellular signals even in the absence of EGF

• EGF (epidermal growth factor) is a small protein that stimulates cell division
• erb-B is an oncogene that encodes a modified form of the EGF receptor
• in these onogene-derived receptors, an intracellular stimulatory signal is produced even in the absence of EGF
• breast cancer cells often contain mutant erb-B receptors

• when bound to GTP, RAS activates protein kinase cascades
• it can normally hydrolyze bound GTP --> switching itself into an inactive GDP-bound form
• type of G protein (cytoplasmic signaling molecule)

ACTIVE!

mutations in the GTPase domain of RAS will reduce the protein's ability to hydrolyze GTP; this results in constitutively active RAS and constantly occuring protein kinase cascades

a tumor suppressor gene; it contains a GAP (GTPase activating protein) domain

Neurofibromin

• NF1 deletion mutations lead to a loss in neurofibromin GAP domain activity
• As a result, neurofibromin can't hydrolyze RAS' GTP, meaning RAS will be "stuck" in its on position excessively signaling to the nucleus

• complex composed of transcription factors Fos and Jun; they form a heterodimer prior to binding to DNA
• AP1 binds promoter and enhancer elements and induces growth-dependent genes

a mutation that will affect the transient nature of Fos and Jun expression may lead to constitutive expression of these proteins; as a result, cell growth will be continuous instead of transient

MYC

a transcription factor that binds to enhancer sequences (e-boxes) & recruits histone acetyltransferases (HATS), regulating the expression of many genes; forces cells through the cell cycle

• The mutation is a reciprocal translocation between the c-myc gene and the immunoglobin heavy chain genes (IgH)
• the result is an over-expression of Myc and more MYC being made than usual

• caused by a translocation between chromosome 8 and either of 2,14 and 22, chromosomes that contain genes encoding antibody molecules
• when translocated, the Myc gene is constitutively expressed

p53 and pRb; removes the breaks and therefore transcription and cell division are more unregulated than they should be

p53

pRB

The viral E7 protein binds to pRB to induce the release of the E2F transcription factor, allowing E2F to bind promoters & activate the transcription of genes in an unregulated manner

The viral E6 protein binds to human p53 and induce the proteolysis of p53 via the ubiquitin pathway. This allows the cell to both go through the cell cycle without checking for DNA damage & evade apoptosis.

E1

E2

• 1. Self sufficiency through growth signals (eg. RAS activation)
• 2. Insensitivity to anti-growth signals (eg. loss of pRB, retinoblastoma suppressor)
• 3. Evasion of apoptosis (produce IGF survival factor, or missing or mutated p53)
• 4. Limitless replicative potential (eg. telomerase activation)
• 5. Sustained angiogenesis (constant blood supply to tumor; VEGF)
• 6. Metastasis and tissue invasion

APC --> no apoptosis, no cellular breaks, full blast acceleration

the spread of cancer from one part of the body to another

reversible phosphorylation

The 7 trans-membrane spanning receptors. This large class of receptors are also known as 7TM receptors and GPCRs (G-protein coupled receptors).