Just in Time Unit 1 Flashcards
define mitogen
induces cells to proliferate
How does a growth factor “tell” a cell to start proliferating?
GF carry specific biological messages and are secreted by cells to “tell” other cells to start proliferating. A single cell can’t make the decision on its own to start proliferation so cell communication is required where cells respond to the presence of GF and prolif.
How are EGFR and ErbB2 (HER2 or Neu) similar?
- EGFR cell surface receptor protein for EGF that recognizes EGF in extracellular space, binds to it, and informs intracellular region
- sequence of EGFR closely related to erbB oncogene
- erbB –> oncoprotein that lacks N terminal ectodomain seq in EGFR (truncated version)
- this version = HER2, “close cousin” EGFR
How are EGFR and ErbB2 (HER2) different?
truncated HER2 version results in cancer because releases similar signals as EGRF but convey constant growth stimulating signals for constant proliferation
Define autocrine signaling and describe how it relates to cancer
signaling loop in which cell manufactures its own mitogens
-tumor cells acquire ability to make a ligand for GFR they display
What is the result of GF dimerization?
dimerization–> cytoplasmic portions of receptor mol joined together
- kinase domain phosphorylates tyrosine (transphosphorylation)
- results (catalytic clef no longer blocked and P occurs)
How are guanine exchange factor proteins (GEFs) and GTPase activating proteins (GAPs) involved in regulating the activity of Ras
Ras binds and hydrolyzes guanosine nucleotides (GTPase). When inactive, Ras binds GDP and active binds GTP. GEFs stimulate inactive GDP/Ras to release GDP and bind GTP, turning on Ras. GTPase hydrolyzes GTP to GDP through GAPs,
What is a problem that can occur with the turning of Ras on and off?
oncogenic point mutation stops GTPase activity leaving Ras continuously on
How is the effector loop of Ras evolved in Ras signaling?
part of Ras protein that physically interacts with effector proteins leading to activation, tight binding with active Ras and no affinity for inactive
What are the downstream effects of Raf signaling?
- Raf kinase
- PI3 kinase pathway
- (Ral-GEF) Ral A/B
the PI3K signaling pathway is unique in that it involves signaling molecules that aren’t proteins. What are these signaling molecules that are termed second messengers?
intracellular hormones that aid with intracellular communication, IP3 and DAG
What is the function of Raf-GEFs?
-mediate the communication between Ras and Ral, stimulate Ral protein to bind GTP and active Ras
Ras + RalGEF =
localization near the membrane and activation of GEF activity–> Ral proteins with downstream signaling effects
define anchorage independent growth
transformed cells able to proliferate without being attached to a solid substrate
Why is anchorage independent growth an important feature for cancer cells?
if cells grow without attaching to solid substrate, good predictor of ability to form tumors…normal cells have to be attached with ECM components to proliferate but cancer cells don’t (proliferation easier at higher level)
How does a cell sense whether or not it is attached to something?
specialized receptors (pair of RTKs) and integrins
describe integrins and cell tethering
components of ECM are ligands of integral surface receptors where specific ECM components bind ectodomain of integrin, forms focal adhesions –> prolif
How is the Jak-STAT signaling pathway similar to the EGFR signaling pathway?
ligand activates receptor via dimerization, Jaks transphosphorylate each other similar to EGFR pathway, both activate Ras-MAPK
what are the two signaling pathways that beta-catenin is associated with?
- E cadherin
- Wnt
why is the cancer phenotype recessive?
normal cell + cancer fueled, hybrid is tumorigenic so inducing of tumor is recessive
How does familial retinoblastoma differ from sporadic retinoblastoma on a genetic level and in how the disease appears in an affected patient?
sporadic- one eye, receive two WT alleles so two mutations must occur to get disease, not passed on
familial- two eyes, receive one mutated allele from parent and one WT, only one mutation has to occur to have bilateral form
Define loss of heterozygosity (LOH)
LOH is the genetic alteration of a gene or chromosomal region
What is one way in which LOH can occur?
gene conversation- during DNA rep, DNA strand hybridizes with complementary instead of template of homologous chromosome, then returns to template but has mixed DNA seq
in general, what are some of the functions of tumor suppressor genes in normal (non-cancerous) cells?
suppress cell prolif
- Direct: growth inhibition or diff inducing signal
- Indirect: cell control and metabolic imbalance
What is the function of NF1?
inhibit Ras signaling through neg feedback by converting Ras from active GTP bound to GDP inactive
VHL in different O2 conditions
normal: HIF1a destroyed
hypoxic: HIF1a accumulates at high levels, turn on transcription, active VEGF
In general, what is the function of the cell cycle checkpoints?
manage cell growth and division so too much prolif doesn’t occur (reduce errors and repetition)
What is the restriction point? When does it occur?
cell must decide whether to remain in G1, leave and go to G0, or go to S (several hours before G1/S transition)
Levels of cyclin proteins (other than D type cyclins) will gradually increase, and then rapidly decline. How is the rapid decline of cyclin proteins (other than D type) achieved?
ubiquitin ligases attach polyubiquitin chains to the cyclins, this polyubiquitylation leads to proteolytic breakdown in the proteosomes
How are the levels of D type cyclins regulated?
mitogenic GF
-stim signal cascade rapid inc, remove GF rapid dec
Are CDK inhibitors considered oncogenes or tumor suppressor genes?
tumor suppressor because CDK inhibitors prevent continuations of complex activity and cell cycle…“put the brakes on” cell cycle activity like tumor suppressors “put the brakes on” prolif
what is the function of pRb?
provide the mechanism for the R point transition, regulate cell prolif, growth suppressor
**blocks transcription by activating enzymes to remove acetyl groups from histone proteins
how is pRb function controlled by its phosphorylation status?
hypo vs hyperphosphorylation
**when hyper, pRb not bound to E2F so E2F acts as transcription activator, + feedback loops
Which proteins are responsible for phosphorylating pRb?
D type cyclins and CDK4/6 kinase partners (hypo) vs cyclin E/CDK2 (hyper)
