C2006/F2402 '06 OUTLINE OF LECTURE #14

(c) 2006 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 03/06/2006 06:08 PM .

Handouts: Need 13B (Cell cycle revisited); 14A (Hormones)

    A.  Types of Mutations that cause cancer (summary from last time)

1. Convert proto-oncogene to oncogene

a. Examples: Changes in genes for ras (so it's always in active form), or GF (always produced as autocrine), or GF receptor (always activated even without GF present), etc.

b. Oncogene can "over do it" 2 ways (see Becker fig. 24-15)

(1). Gene can be overexpressed  -- Protein is normal, but you make too much of it (or you make it at the wrong time/place). Mutation is in regulatory sequence controlling gene, not in coding part. (ex: constitutive production of a GF)

(2). Gene can be altered so protein made is constitutively active -- Normal amount of protein is made, but protein is altered. (ex: production of altered GF receptor that is active without its ligand.)

2. Inactivation of Tumor Suppressors

a. Normal "brake" genes are called tumor suppressors (see Purves 17.17 (18.17) for picture or Becker table 24-2 (17-3) for a list)

b. Examples: Most famous examples = rb and p53. 

(1). p53 -- Normal p53 acts as 'brake' on activation of CDK/cyclin complex in damaged cells. (see Becker fig. 19-39 (17-40))

(2b). rb --  rb protein must be phosphorylated (and inactivated) for cell to enter S.  Rb 'holds up' the cycle until CDK/cyclin complex is properly activated. (See handout and Becker fig. 19-38 (17-36)). 

c. How mutation causes cancer: When tumor suppressor is defective, cell keeps on growing when it should not -- in spite of damage (p53) or lack of growth factor signal (rb), etc. Result is often a tumor.

    B. How do Cancer Causing Mutations occur?

1. Somatic mutations can cause cancer (see Becker fig. 24-12)

a. What's a somatic mutation? A mistake in DNA replication that occurs in somatic cells, not in germ cells. Is not inherited or passed on.

b. Changes in Regulation. Genes can become over-active [or inactive] because of rearrangements or other mutations that alter effects of enhancers, silencers, etc. Example of cancer caused by rearrangements of regulatory sequences: Burkitt's lymphoma. (Proto-oncogene is placed next to a very strong enhancer.) See Becker fig. 24-13.

c. Changes in Protein Structure. Protein can become over-active [or inactive] because of changes in the gene that alter the amino acid sequence of the protein. Example caused by rearrangement: chronic myelogenous leukemia (CML -- too many white blood cells) -- cells make a hybrid, constitutively active TK instead of normal TK whose activity is regulated. See Becker Fig. 24-14 & 24-15.

2. Viruses can cause cancer --  viral DNA integrates into normal cell DNA and brings in new genes (or messes up old ones of host).

a. Virus can carry in a new gene/protein -- an oncogene or a gene that codes for the inhibitor of a tumor suppressor. See Becker fig. 24-18.

b. Virus DNA can destroy a host gene -- virus can integrate into DNA in middle of a normal gene and inactivate that gene -- can knock out a tumor suppressor.

c. Virus DNA can carry in a new regulatory sequence -- virus can integrate into DNA near a normal host gene and provide an enhancer or silencer that changes expression of that host gene -- can turn on a proto-oncogene.

d. Most cancers are not caused by viruses. A few types of cancer are associated with viruses (see Purves Table 17.1 (18.2)) but even in these cases the viruses alone are usually not sufficient to cause the cancer. An example: Cervical cancer is largely viral in origin, in that HPV infection is usually involved. However HPV infection is not sufficient to cause it. HPV makes a protein that inactivates rb protein.   (Note: there is some recent evidence that some cases of prostate cancer are associated with a viral infection. See also medpage for a reference to the original report.)

3. You can inherit a predisposition to cancer, not the disease itself. How can you inherit a "predisposition" = high chance of getting cancer?

a. Genes that affect DNA replication &/or repair.  If you inherit versions of genes giving low repair or high mutability, tend to get cancer -- sooner or later, one of the random mutations that occurs is likely to mess up a proto-oncogene or tumor suppressor gene as above. Example: xeroderma pigmentosum, which carries a high risk of skin cancer because of defects in the genes for DNA repair. See Becker, box 24A & fig. 24A-1.

b. Tumor suppressor mutations. If you inherit one defective copy of a tumor suppressor gene, nothing happens unless the second copy of the gene gets messed up in a cell. If both copies of a tumor suppressor gene in one cell get inactivated or lost, cancer can result.  (This is the "two-hit" hypothesis for how mutated tumor suppressors cause cancer. See Purves 17.16 (18.16) or Becker fig. 24-17. Example: retinoblastoma, which causes a high risk of eye and ovarian tumors, is caused by defects in rb.

4. Most cancer is sporadic, due to somatic mutation. Not inherited.

5. Cancer develops in stages

a. Most cancers have more than one mutation

b. Selection -- selection for increasing loss of growth control occurs as disease progresses -- cells that grow more aggressively (due to additional mutations) outgrow the others.

c. Progression: Normal cell --> benign tumor --> malignant (invasive) --> metastasis (spreads) See Purves 17.18 (18.18) or Becker fig. 24-10.

d. What sort of mutation causes cancer? Is cancer caused by a 'lack of function' mutation or 'gain of function' mutation? Usually both.

Try problems 15-3 & 15-4.

     C. How do Rb & p53 fit into normal cycle? How do mutant tumor suppressor genes/proteins cause cancer.

3. Rb vs p53: p53 regulates activation of CDK/cyclin complex. Rb is phosphorylated by active complex. So rb acts "downstream" of p53 = after p53, at a later step in the pathway. If rb is out of commission, it doesn't matter what p53 does -- p53 can't block the cycle.

Note: the real situation is quite complex and there is some evidence that ras may also directly effect rb without cyclin. This complexity and/or uncertainty is reflected in your texts -- the different diagrams in the texts differ in where they put cyclin relative to rb/E2F. Hopefully, this matter will be cleared up shortly and the information we get will be useful in preventing growth of cancerous cells.

Try Problems 15-2, 15-5, & 15-6.

II. Introduction to Hormones (Primarily Endocrines)

III. How to Keep Track of Hormones --  How to Classify Hormones & Growth Factors (or Signal Molecules in General). The following is meant as a check list to help you keep track of the various signal molecules. It is for reference & study purposes; it will not be discussed in class.
    Some of these questions/categories overlap, and you can't answer all the questions for all the hormones, growth factors, etc., but the list helps to organize the information you do have.

1. Type of Action -- Is it paracrine, endocrine (hormone), growth factor, neurotransmitter, etc.? (See handout 11B or Purves Table 42.1 (41.1 )

2. Chemical nature -- Is it a peptide, amino acid or derivative, fatty acid or derivative, or steroid? See Becker table 14-4.

3. Where is it made? In what gland or tissue? (HT? pancreas?)

4. Target Cells -- where does it act? (Muscle and liver or just liver?)

5. Mechanism of signal transduction

A. Location/type of receptor on target cells -- Is receptor on surface or intracellular? TK or G protein linked?

B. Type of signal transduction -- Is there a second messenger? Which one? If none, what links receptor to intracellular events?

C. Intracellular mode of action -- Is there a change in enzyme activity? change in transcription? both? change in state of ion channel? = not what happens, but how?

6. What actually gets done? What happens?

A. Biochemically speaking: Which enzymes, proteins or genes are affected (glycogen phosphorylase activated? Cyclin gene transcribed?)

B. Physiological End Result: Another hormone secreted? Glycogen broken down, & Glucose in blood up? Note the "result" may have several steps, and more than one can sometimes be considered "the end."

C. What's the (teleological) point? What overall function is served by the signal molecule's action?

1. One list of possibilities: Homeostasis, response to stress, growth, maintenance of some cycle;

2. An alternative version of the list: Regulation of rates of processes, growth & specialization, Conc. of substances, and response to stress.

3. The 2 lists are really the same = homeostasis (control of rates & concentrations), response to stress, & regulation of  growth (unidirectional and cyclic).

a. Release hormones into portal vessel (connects two capillary beds) that goes direct to anterior pituitary. See Purves 42.7 (41.7) and handout 14A.

b. Hormones are release factors. Hormones released by HT affect production/release of other hormones by ant. pit.

c. Affect on release -- 'release factors' can be stimulatory (RH's such as ACTH-releasing hormone) or inhibitory (IH's such as prolactin release-inhibiting hormone = PIH) For a complete list see Purves Table 42.2 (41.2).

d. All HT hormones (except PIH = dopamine) are peptides/proteins

1. Tropic Hormones (for names of hormones and target cells see handout 14A & table below)

a. Made by ant. pit and influence other endocrine glands

b. Release controlled by hormones from HT

c. Effect on target tissue

(1). Effect: Usually cause release of another hormone

(2). What is released? Hormones released by targets are steroids or act like them (thyroxine)

(3). Mechanism: All tropic hormones work through G linked receptors and cAMP.

d. Three major tropic hormone types -- each type named after its target -- see handout 14A & table below.

2. Other Hormones of ant. pit.

a. GH and prolactin -- "pseudo tropic" hormones

(1). Structure & mechanism: Similar in structure to each other (homologous) and use a special type of TK receptor

(2). What is released? Stimulate production of secretions, but not from endocrine glands.

(a). GH stimulates liver (& possibly other tissues) to produce insulin-like growth factors (ILGF 1 & 2); ILGF's from liver released into blood (act as endocrines); ILGF's from other tissues act as paracrines. (GH has other effects as well.)

(b). Prolactin stimulates mammary (exocrine) gland to produce milk. (Need oxytocin to eject the milk.)

b. MSH etc.

(1). Common source: All come from cleavage of single peptide precursor (pro-opio-melanocortin or pomC) that is cut up to give ACTH and MSH etc.

(2). Alternative ways of cleavage: Same precursor can be cut up different ways in different tissues and/or species. Note: this is alternative processing of a protein, not an RNA.

(3). Function: Function of these hormones relatively obscure.

3. Summary of Tropic & Pseudo-tropic Hormones of Ant. Pit.