Neoplasia #4: Oncogenes and the Cell Cycle

Review of cell categories

Cell cycle

G0 = arrest phase of cell

G1 = all cell content expect chromosomes are duplicated

S = chromosomal replication

G2 =1,000,000 mg² integrity of duplicated genome is checked and corrected

M = mitosis

Growth factors coax cells in G0 back into G1

Restriction point: cell irreversibly committed to cell cycle progression or apoptosis

Control of the cell cycle

CDK (cyclin dependent kinases) help cells through cell cycle by binding to cyclins

Loss of cell cycle control is essential for malignancy

At least one of the 4 cycle regulators CDK4, RB, CDK1, p16, or cyclin D is dysregulated in the majority of cancers

Define proto-oncogenes

Group of genes that can cause normal cells to become cancerous when they are mutated

• They are normal in the unmutated state → controlled cell growth. 

How do proto-oncogenes function?

1. Activation of guanine binding protein

2. Activation of tyrosine kinase

Conversion of proto-oncogenes to oncogenes (c-one) occurs by three mechanisms

1. Point mutation

2. Translocation

3. Amplication (also over expression)

Oncogenes are genes whose products are associated with

neoplastic transformation

Mechanisms of oncogene activation

Oncogenes encode __ that are similar to normal counterparts. 

Oncogenes encode oncoproteins that are similar to normal counterparts.

• They are constantly active = never turned off = unregulated

Oncoproteins can promote

cell growth in the absence of normal growth signals. 

What mutation constitutes the most common type of abnormality involving proto-oncogenes?

Point mutations of the RAS family genes constitute the most common type of abnormality involving proto-oncogenes. 

• 15-20% of all human tumors express mutated RAS proteins

• 90% of all pancreatic adenocarcinomas are associated with KRAS

  • Think: panKReAS

Downstream RTK mutations - RAF/BRAF

Causes hairy cell leukemia and melanoma

Downstream RTK mutations - PI3K

Causes breast carcinoma

Downstream RTK mutations - PTEN

Causes endometrial carcinoma

What are non-receptor tyrosine kinases?

Localized to the cytoplasm or the nucleus

Many are mutations of chromosomal translocation or rearrangements → creates fusion genes encoding constitutively active tyrosine kinases

Oncogenic activation by chromosome translocation - over expression of proto-oncogene

• t(8; 14) - Burkitt lymphoma-C (c-MYC)

• t(14;18) - Follicular lymphoma (Bcl-2)

Oncogenic activation by chromosome translocation - fusion/chimeric genes

Novel product promotes cell proliferation in same manner as an oncogene

• t (9;22) - Chronic myeloid leukemia

• t (15;17) - acute promyelocytic leukemia (AML B3)

• t(11;22) - Ewing sarcoma

Philadelphia chromsome

CML:

• BCR -ABL1 fusion gene

• 9 and 22 translocation

Creates fusion gene → continuous activation of tyrosine kinase pathway → increased cell growth → decreased apoptosis

Also associated with some ALL

In CML, how to G1-S checkpoint stimulated?

ABL tyrosine kinase activity is constitutively activated by the juxtaposition of BCR, thus favoring autophosphorylation

Important translocations need to know - Burkitt lymphoma

c-MYC translocation

Also has amplification → worse prognosis

Important translocations need to know -

Important translocations need to know - Acute promyelotic leukemia

PML-RAR alpha, transcription factor

Important translocations need to know - Synovial sarcoma

(X:18)

SYT-SSX

Important translocations need to know -

Important translocations need to know - Renal cell carcinoma

Xp11 (X:17)

AND ALSO

alveolar soft parts sarcoma

Important translocations need to know - Ewing Sarcoma

EWS-FLI1

transcription factor

MYC amplification

MYC is amplified in many cancers - breast, colon, lung

• N-MYC amplified in neuroblastoma

• c-MYC activated by chromosomal translocation in Burkitt’s lymphoma

Extra chromosomal double minutes

Oncogene

MUST KNOW ONCOGENE AND WHAT IT CODES FOR!!!!!