Just in Time Unit 1

Question 1

define mitogen

Answer 1

induces cells to proliferate

Question 2

How does a growth factor “tell” a cell to start proliferating?

Answer 2

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.

Question 3

How are EGFR and ErbB2 (HER2 or Neu) similar?

Answer 3

• 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

Question 4

How are EGFR and ErbB2 (HER2) different?

Answer 4

truncated HER2 version results in cancer because releases similar signals as EGRF but convey constant growth stimulating signals for constant proliferation

Question 5

Define autocrine signaling and describe how it relates to cancer

Answer 5

signaling loop in which cell manufactures its own mitogens

-tumor cells acquire ability to make a ligand for GFR they display

Question 6

What is the result of GF dimerization?

Answer 6

dimerization–> cytoplasmic portions of receptor mol joined together

• kinase domain phosphorylates tyrosine (transphosphorylation)
• results (catalytic clef no longer blocked and P occurs)

Question 7

How are guanine exchange factor proteins (GEFs) and GTPase activating proteins (GAPs) involved in regulating the activity of Ras

Answer 7

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,

Question 8

What is a problem that can occur with the turning of Ras on and off?

Answer 8

oncogenic point mutation stops GTPase activity leaving Ras continuously on

Question 9

How is the effector loop of Ras evolved in Ras signaling?

Answer 9

part of Ras protein that physically interacts with effector proteins leading to activation, tight binding with active Ras and no affinity for inactive

Question 10

What are the downstream effects of Raf signaling?

Answer 10

• Raf kinase
• PI3 kinase pathway
• (Ral-GEF) Ral A/B

Question 11

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?

Answer 11

intracellular hormones that aid with intracellular communication, IP3 and DAG

Question 12

What is the function of Raf-GEFs?

Answer 12

-mediate the communication between Ras and Ral, stimulate Ral protein to bind GTP and active Ras

Question 13

Ras + RalGEF =

Answer 13

localization near the membrane and activation of GEF activity–> Ral proteins with downstream signaling effects

Question 14

define anchorage independent growth

Answer 14

transformed cells able to proliferate without being attached to a solid substrate

Question 15

Why is anchorage independent growth an important feature for cancer cells?

Answer 15

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)

Question 16

How does a cell sense whether or not it is attached to something?

Answer 16

specialized receptors (pair of RTKs) and integrins

Question 17

describe integrins and cell tethering

Answer 17

components of ECM are ligands of integral surface receptors where specific ECM components bind ectodomain of integrin, forms focal adhesions –> prolif

Question 18

How is the Jak-STAT signaling pathway similar to the EGFR signaling pathway?

Answer 18

ligand activates receptor via dimerization, Jaks transphosphorylate each other similar to EGFR pathway, both activate Ras-MAPK

Question 19

what are the two signaling pathways that beta-catenin is associated with?

Answer 19

• E cadherin

- Wnt

Question 20

why is the cancer phenotype recessive?

Answer 20

normal cell + cancer fueled, hybrid is tumorigenic so inducing of tumor is recessive

Question 21

How does familial retinoblastoma differ from sporadic retinoblastoma on a genetic level and in how the disease appears in an affected patient?

Answer 21

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

Question 22

Define loss of heterozygosity (LOH)

Answer 22

LOH is the genetic alteration of a gene or chromosomal region

Question 23

What is one way in which LOH can occur?

Answer 23

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

Question 24

in general, what are some of the functions of tumor suppressor genes in normal (non-cancerous) cells?

Answer 24

suppress cell prolif

• Direct: growth inhibition or diff inducing signal
• Indirect: cell control and metabolic imbalance

Question 25

What is the function of NF1?

Answer 25

inhibit Ras signaling through neg feedback by converting Ras from active GTP bound to GDP inactive

Question 26

VHL in different O2 conditions

Answer 26

normal: HIF1a destroyed
hypoxic: HIF1a accumulates at high levels, turn on transcription, active VEGF

Question 27

In general, what is the function of the cell cycle checkpoints?

Answer 27

manage cell growth and division so too much prolif doesn’t occur (reduce errors and repetition)

Question 28

What is the restriction point? When does it occur?

Answer 28

cell must decide whether to remain in G1, leave and go to G0, or go to S (several hours before G1/S transition)

Question 29

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?

Answer 29

ubiquitin ligases attach polyubiquitin chains to the cyclins, this polyubiquitylation leads to proteolytic breakdown in the proteosomes

Question 30

How are the levels of D type cyclins regulated?

Answer 30

mitogenic GF

-stim signal cascade rapid inc, remove GF rapid dec

Question 31

Are CDK inhibitors considered oncogenes or tumor suppressor genes?

Answer 31

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

Question 32

what is the function of pRb?

Answer 32

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

Question 33

how is pRb function controlled by its phosphorylation status?

Answer 33

hypo vs hyperphosphorylation

**when hyper, pRb not bound to E2F so E2F acts as transcription activator, + feedback loops

Question 34

Which proteins are responsible for phosphorylating pRb?

Answer 34

D type cyclins and CDK4/6 kinase partners (hypo) vs cyclin E/CDK2 (hyper)