Ogan Gurel, MD

Biology 301
Lecture # 13
Roosevelt University

Biology 301
Cellular and Molecular Biology
Spring 2002

Lecture # 13: Eukaryotic Gene Expression II

 Ogan Gurel, MD
Biology 301
Lecture # 13
Roosevelt University

Overall outline
 Review of Eukaryotic Genomes
 Transcription regulation
 Cancer
 Ogan Gurel, MD
Biology 301
Lecture # 13
Roosevelt University

Review of Eukaryotic Genomes

Chromatin
Structural levels in chromatin
Types of repetitive DNA
The evolution of human α-globin and β-globin
DNA rearrangements in immunoglobulin gene
expression
 Ogan Gurel, MD
Biology 301
Lecture # 12

Chromatin
Roosevelt University
Structural levels in Ogan Gurel, MD
Biology 301
Lecture # 12

chromatin
Roosevelt University
 Ogan Gurel, MD
Biology 301
Lecture # 12

Types of repetitive DNA

Roosevelt University
The evolution of human α-
Ogan Gurel, MD
Biology 301
Lecture # 12
Roosevelt University

globin and β-globin

DNA rearrangements in
Ogan Gurel, MD

immunoglobulin gene Biology 301

Lecture # 12
Roosevelt University

expression
 Ogan Gurel, MD
Biology 301
Lecture # 13
Roosevelt University

Eukaryotic transcription
regulation
 Points of regulation
 Transcription & translational level control
 “Action at a distance”
 Protein – DNA interactions mediate regulation
 Ogan Gurel, MD
Biology 301
Lecture # 12

Points of regulation
Roosevelt University

• Chromatin

• RNA processing

• Transport

• Translation

• Protein processing
 Ogan Gurel, MD

Transcription & translational level

Biology 301
Lecture # 12
Roosevelt University

control
 Ogan Gurel, MD
Biology 301
Lecture # 12

“Action at a distance”
Roosevelt University
Protein – DNA interactions Ogan Gurel, MD
Biology 301
Lecture # 12

mediate regulation
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A
 Ogan Gurel, MD
Biology 301
Lecture # 13
Roosevelt University

Cancer
 Carcinogenesis is a multistep process
 Which implies changes in multiple cellular functions
 Which can be grouped into oncogenes & tumor
suppressor genes
 Oncogenes can be “activated” in a number of ways
 Carcinogenesis is a Ogan Gurel, MD
Biology 301
Lecture # 12

multistep process
Roosevelt University

Normal
FAP epithelium Metastasis

Hyperprolifer.
epithelium
DNA hypo-
methylation
Early
adenoma
K-ras
Intermediate
adenoma
DCC ?
Metastasis
Late
p53 adenoma

Invasive
Carcinoma

Neoplasia

Sources: Adapted from Ringer & Schnipper, (2001), “Principles of Cancer Biology,” In: Clinical
Oncology – American Cancer Society, p. 30; Fearon & Vogelstein, (1990), “A genetic model of
Other
colorectal tumorigenisis,” Cell, 61: 759; Weinberg (1996), “How Cancer Arises,” Scientific American. alterations
 Which implies changes in Ogan Gurel, MD
Biology 301
Lecture # 12

multiple cellular functions

Roosevelt University

Retinoblastoma, bone, bladder, lung, breast

Colon

Some neural tumors

Brain Many cancers

Sarcomas

Leukemia

Leukemia, brain, breast,

stomach, lung
Which can be grouped into Ogan Gurel, MD

oncogenes & tumor suppressor

Biology 301
Lecture # 12
Roosevelt University

genes
Oncogenes Tumor Suppressors
Genes for growth factors or their receptors Genes for proteins in the cytoplasm
Codes for platelet-derived growth factor. Involved in glioma (a
PDGF brain cancer) APC Involved in colon and stomach cancers

Codes for the receptor for epidermal growth factor. Involved in Codes for a relay molecule in a signaling pathway that inhibits cell
erb-B glioblastoma (a brain cancer) and breast cancer DPC4 division. Involved in pancreatic cancer

Also called HER-2 or neu. Codes for a growth factor receptor.
erb-B2 Involved in breast, salivary gland and ovarian cancers
RET Codes for a growth factor receptor. Involved in thyroid cancer
Genes for cytoplasmic relays in stimulatory
signaling pathways
Codes for a protein that inhibits a stimulatory (Ras) protein.
NF-1 Involved in neurofibroma and pheochromocytoma (cancers of the
peripheral nervous system) and myeloid leukemia
Involved in meningioma and ependymoma (brain cancers) and
NF-2 schwannoma (affecting the wrapping around peripheral nerves)
Genes for proteins in the nucleus

Ki-ras Involved in lung, ovarian, colon and pancreatic cancers

MTS1 Codes for the p16 protein, a braking component of the cell cycle
clock. Involved in a wide range of cancers

N-ras Involved in leukemias

Codes for the pRB protein, a master brake of the cell cycle. Involved
RB in retinoblastoma and bone, bladder, small cell lung and breast
Genes for transcription factors that activate cancer

growth-promoting genes Codes for the p53 protein, which can halt cell division and induce
p53 abnormal cells to kill themselves. Involved in a wide range of
c-myc Involved in leukemias and breast, stomach and lung cancers cancers

N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma WT1 Involved in Wilms' tumor of the kidney

L-myc Involved in lung cancer Genes for proteins whose cellular location is not
yet clear
Genes for other kinds of molecules
BRCA1 Involved in breast and ovarian cancers
Codes for a protein that normally blocks cell suicide. Involved in
Bcl-2 follicular B cell lymphoma
BRCA2 Involved in breast cancer

Also called PRAD1. Codes for cyclin D1, a stimulatory component

Bcl-1 of the cell cycle clock. Involved in breast, head and neck cancers VHL Involved in renal cell cancer

Codes for an antagonist of the p53 tumor suppressor protein.

MDM2 Involved in sarcomas (connective tissue cancers) and other
Source: Adapted from Weinberg (1996), “How Cancer Arises,”
cancers
Scientific American.
Oncogenes can be
“activated” in a number of Ogan Gurel, MD
Biology 301
Lecture # 12

ways
Roosevelt University
Complex pathways cause Ogan Gurel, MD
Biology 301
Lecture # 12

“downstream” effects
Roosevelt University
 Which can serve as the Ogan Gurel, MD
Biology 301
Lecture # 12

basis for future therapeutics

Roosevelt University

Approved by the FDA (May 2001) on the basis of

clinical results (98% of patients experienced a complete
remission of leukemic cells) … and for a rare cancer
gastrointestinal stromal tumor (GIST)
Sources: Druker BJ, Talpaz M, Resta DJ, et al. (2001) “Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase
in chronic myeloid leukemia,: N Eng J Med 344:1031-1037;
Novartis prescribing information (http://www.pharma.us.novartis.com/product/pi/pdf/gleevec.pdf);
NCI press release (http://newscenter.cancer.gov/pressreleases/gleevecpressrelease.html)