Cancer

Alberts et al., chapter 24

There have been some break-throughs:
E. Culotta & D.E. Koshland, Jr., p53 sweeps through cancer research (molecule of the year) Science 262, 1958-1959, 1993, also editorial "Molecule of the year" p. 1953 and cover
also 2 breast cancer genes isolated (BRCA 1 and 2, see below for where they fit into the whole regulation of cell integrity)
Remember involvement of patched (hedgehog pathway) in basal cell carcinoma => relevance of cancer in a signal transduction course

M. Barinaga, From benchtop to bedside, Science 278, 1036-1039, 1997
TRANSPARENCY - discuss how drug design might be addressed to altering something like fatty acid group added to ras

Here I duplicate some fundamental information from the eye development lecture:
tyrosine kinase signalling
small G protein
sevenless signalling pathway
Boss = bride of sevenless is 7 transmembrane domain ligand
sevenless is receptor tyrosine kinsae -
2 transmembrane subunits, 2 extracellular subunits
It is a topic of intense present interest how this signals across membrane
Drk = downstream of receptor tyrosine kinase
which is a small SH adaptor protein, SH = src homology
src = oncogene of Roux sarcoma virus
Sos = son of sevenless
which is a GNRP (guanine nucleotide releasing protein)
to exchange GTP for GDP on ras
ras = rat sarcoma [viral ras oncogene of normal protooncogene]
ras is actually linked to membrane by fatty acid
GAP (sextra in Drosophila) does opposite (GTPase activating protein)

General and fundamental points:
carcinoma - epithelial cell
sarcoma - muscle or connective tissue
leukemia - hemopoeitic cells
carciongenesis and chemicals like aflatoxin (sometimes modified by metabolism) alter DNA in a single cell
other chemicals promote tumors by encouraging cell division or discouraging terminal differentiation - like phorbol esters which activate PKC
tumor=neoplasm, benign vs malignant, metastases to secondary tumors
carcinoma crosses basal lamina to metastasize
angiogenesis is very important
although there is not much mention in the chapter, regulation of apoptosis and immune surveillance are also very inportant

The retinoblastoma story
1 / 20,000 children have it
hereditary form has multible tumors in both eyes from neural precursor cells
non-hereditary - one eye - one tumor
both have deletion in chromosome 13. deletion => loss of a tumor suppressor
TRANSPARENCY - Fig. 24-29, p. 1282 - shows genetics
unphosphorylted Rb binds to proteins, keeping them from allowing DNA replication
Of course, cell division and its regulation should be involved
Tumor suppressor - these would be harder to find than genes that cause cancer (below)

The p53 story (another tumor suppressor)
discovered in 1979, molecule of the year in 1993
hard to see missense mutations on Southern blots
6.5 million cancer diagnoses per year, half have mutations in p53
p53 mutant in many types of cancers, aggressive ones
"53" signifies 53 kDa
p53 is a transcription factor, binds DNA, induces transcription of gene for 21kDa protein
p21 binds and blocks kinase activity of complex (G1 cyclin - Cdk2)
p53 (&p21) thus halt cell cycle at G1 checkpoint (before going onto S phase)
p53 is high in cells insulted with UV or ionizing radiation
human papilloma virus (cervical cancer) targets p53
p53 triggers programmed cell death in cells with DNA damage
with p53 mutation there is abnormal cell growth
knockout is born normal but has tumors or dies by 6 mo

E.R.Fearon, Human cancer syndromes: Clues to the origin and nature of cancer, Science 278, 1043-1050, 1997
"syndromes" -- this paper is dealing with genetic tendencies
gain of function = oncogenme, both alleles loss of function = tumor suppressor
There is an informative table, and the cloned genes include RB1 (retinoblastoma), p53, APC (adenomatous polyposis coli), BRCA 1 & 2 (breast cancer)
colorectal cancer - other tumor suppressors:
APC (familial adenomatous polyposis coli)
DCC (deleted in colon carcinoma)
HNPCC (hereditary non-polyposis colorectal cancer)
recalling the wnt signalling pathway:
TRANSPARENCY - WNT->Frizzled->DSH (dishevelled)->GSK3 (glycogen synthase kinase)->APC->beta-Catenin

Virus and its relation to cell
(chicken) Rous sarcoma virus - this is a retrovirus - has src gene inactivated
viral form (v-src) was apparently picked up from a cellular form (c-src)
The hallmark of retroviruses is their ability to put and take from the genome
TRANSPARENCY - Table 24-4, p. 1276, demonstrates why cancer is a topic in signal transduction course- kinases, GTP-binding proteins, growth factors, gene regulation proteins
TRANSPARENCY Table 24-5, p. 1277 some other familiar signalling molecules
like bcl-2 and RAR-alpha
Genes that cause cancer (oncogenes) but the idea is that the normal gene should subserve a normal function which is only disrupted if the gene (proto-oncogene) becomes abnormal
TRANSPARENCY Fig. 24-26, places where signalling molecules can be altered in cells in cancer
(including ras, raf, steroid-like receptors, membrane growth factor receptors, growth factors)
TRANSPARENCY elaborates ras material covered earlier with the suggestion that a drug which interferes with farnesyl transferase could help to regulate ras
From M. Barinaga,From bench top to bedside (News), Science 278, 1036-1039
TRANSPARENCY very complex (from Fearson, see above) genes involved:
including hedgehog, patched, smoothened, APC, and many others

From M. Peifer, Cancer, catenins, and the cuticle pattern: A complex connection, Science 262, 1667-1668, 1993
also B Rubinfeld et al., Association of the APC gene product with beta-catenin, Science 262, 1731-1734, 1993
and
L.-K. Su et al., Association of the APC tumor suppressor protein with catenins, Science 262, 1734-1737, 1993
TRANSPARENCY showing earlier model with APC-catenin interaction involved in cadherin of adhering junction involving armadillo = beta-catenin, wingless, etc
reminder from earlier lectures, including Beth Burgwyn's wnt lecture, wnt pathway interacts with notch and hedgehog pathways
Also there are a lot of interactions outside the cell where the ligand interacts with the receptor that make wnt signalling very complex
otherwise, beta-catenin helps transcription by a factor called Tcf-Lef
involvement of APC and GSG which phosphorylate beta-catenin to mark it for ubiquitinization for degradation by the proteasome

This page was last updated on April 16, 2002

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