Cell Growth, Cancer, and Oncogenes

Growth factors are secreted by cells to signal other cells to grow. Some factors promote growth, while others inhibit it.
Serum, found in clotting blood, is rich in growth factors released by platelets during wound healing.
Cells integrate growth and inhibitory signals and decide at checkpoints whether to proceed with the cell cycle.

Epidermal Growth Factor (EGF) binds to tyrosine kinase receptors.
Ligand binding induces dimerization of the receptor, leading to cross-phosphorylation of tyrosine residues.
Activation of the intracellular domain can activate Ras by GDP-GTP exchange (Ras-GDP becomes Ras-GTP).
- Inactive Ras becomes active Ras by losing GDP and gaining GTP.
Ras then activates MAP kinase signaling, a chain reaction where kinases activate each other, ultimately affecting proteins and transcription related to cell growth.

Tumors, like a 1 cubic centimeter tumor ( $10^9$ cells), originate from a single cell that divides uncontrollably (monoclonal growth).
Cancer is a major public health issue, and significant progress has been made in developing new therapies.

Normal cells in culture proliferate in the presence of growth factors until they reach confluency (a packed monolayer).
Contact inhibition: Normal cells stop growing when they touch each other, even with growth factors present.
Transformed cells, however, lose contact inhibition and continue to proliferate, piling up on each other.

Normal cells require anchorage to a surface to proliferate; transformed cells lose this dependence.
Transformed cells may not even need growth factors to proliferate.
Transformed cells often exhibit changes in shape and can cause tumors if introduced into the body.

Carcinogens are chemicals that can lead to cancer.
In cell culture, transformed cells form foci (bumps) that are visible without a microscope.
Testing chemicals for their ability to induce foci formation helps identify carcinogens.
Governmental organizations like the FDA regulate carcinogenic chemicals.
Cancer is caused by mutations in DNA that lead to uncontrolled growth.

A correlation exists between how carcinogenic a chemical is and how likely it is to cause DNA mutations, especially on a log-log scale.

RSV contains genes essential for replication (gag and pol) and a gene responsible for transformation called src.
Wild type RSV (gag, pol, src) causes infection and cancer, while a modified RSV (ΔRSV) lacking src causes infection but not cancer.
This led to the idea that src is an oncogene, introduced into cells to cause cancer.

The initial understanding was that cancer develops when an oncogene is introduced into a cell.
However, it was discovered that the src gene is present in both infected and uninfected chicken cells.
Proto-oncogenes are normal genes that regulate cell growth; they can mutate into oncogenes.
In chickens, the proto-oncogene is called c-src, a tyrosine kinase involved in development, cell growth, and wound healing.
The oncogene version, v-src, exhibits constitutive tyrosine kinase signaling, always phosphorylating downstream proteins and triggering uncontrolled growth.

Ras is a protein that, when bound to GDP is off, and when bound to GTP, is on and triggers downstream pathways for growth.
Ras has intrinsic GTPase activity and so can turn GTP back into GDP, turning itself off.
As a proto-oncogene, Ras is an important growth regulator that turns itself off.
As an oncogene, Ras loses GTPase activity and cannot turn off, leading to constant signaling for cell growth.
30% of human cancers involve a mutation in Ras.

P53 checks for DNA errors before replication and initiates DNA repair or apoptosis (cell suicide).
Loss of P53 function occurs in 50% of human cancers.
P53 is encoded by a gene and we have 2 copies of every gene because we are diploid.
If one copy of the P53 gene is mutated it would not affect the function because there is one functional copy.
Need loss of function in both copies for P53 to fail.
P53 is known as a tumor suppressor gene.

With Ras, only one mutated copy of the gene (lacking GTPase activity) is enough to cause cancer, as some Ras proteins will always be active.
With P53, both copies of the gene must be mutated for it to fail, as some functional P53 is sufficient to prevent uncontrolled growth.
Oncogenes are dominant mutations (only one copy needs to be mutated), while tumor suppressor genes are recessive (both copies need to be mutated).