CD Quiz 1 Summary

Cancer

collection of related diseases; dysregulated cell growth + uncontrollable division

Cancer requires

multiple hits → mutations

Cells can become

neoplastic and acquire hallmark characteristics → leads to tumor formation and metastases

Original Hallmarks of Cancer

resists death, sustains proliferative signaling, evading growth suppressors, activates invasion and metastasis, enables replicative immortality, induces angiogenesis, resists cell death

Normal Cells control

growth-promoting signals and entry into cell cycle → maintains homeostasis

____play an essential role in regulating cell growth

growth factors and tyrosine kinases

Cancer cells cause

continued entry into the cell cycle, autocrine proliferative stimulation, changes RTK abundance and responsiveness (constitutive action), somatic mutations, disruption of negative feedback mechanisms

Growth Factors

regulate cell cycle progression, G1/S transition, G2/M transition by modulating cell size

Restriction Point (Start) Influences

growth factors, nutrients, cell size, DNA damage

G2-M Transition Influences

cell size, DNA damages, DNA replication

Metaphase-Anaphase Transition Influences

chromosome attachments to spindle

Restriction Point Model

textbook model of cell cycle progression; irreversible commitment to complete the cell cycle and become independent of mitogens at G1-S phase transition (the restriction point)

____ are important for regulating the cell cycle

CDK/Cyclin complexes

CDK/Cyclin Complexes are regulated by

p16, p21, and p27

CDKS are only active when

in complex with cyclins

When a cyclin and CDK form a complex

the complex will bind to a target protein and modify it through phosphorylation → phosphorylated target protein will trigger a specific event in the cell cycle → after event occurs cyclin is degraded and the CDK is rendered inactive

Cyclin degradation

tightly regulated during the cell cycle

RB Tumor Suppressors

pocket proteins that exist in pocket domain; paralogs; pocket domain is conserved between different RBs

KRAS Oncogene

most frequently mutated oncogene in human cancer and first confirmed human oncogene in 1982

Three genes

HRAS, NRAS, KRAS encode four major RAS isoforms HRAS, NRAS, KRAS4A, and KRAS4B

KRAS encodes

two variants derived from alternative splicing of exon 4 → divergent C-terminal sequences

KRAS4B

more dominant in human cells

KRAS4A

low expression levels and more similar to viral KRAS

Sotorasib drug

first therapy to directly target the KRAS oncoprotein cancers by inhibiting the switch II pocket which causes the G12C mutation

RAS Proteins

small, membranebound guanine, nucleotide binding GTPases; binary switches that cycle between GTP bound active and GDP bound inactive to regulate signal transduction

GEF Proteins

guanine nucleotide exchange factors

GAP Proteins

GTPase-activating proteins

Missense gene mutations at

aa resides G12, G13, and Q61 have unique structural and functional consequences on the RAS protein; increase RAS activation through locking it in GTP active form → bypass upstream signaling from RTK

Substitution of glycine at G12 or G13 by anything other than P

causes a steric block that stops the arginine finger of GAP from entering GTPase site of RAS → stops hydrolysis

Q61 mutations

abolish intrinsic and GAP mediated GTP hydrolysis

MYC Transcription Factor

regulates various cellular processes and has been implicated in tumorigenesis and drug resistance; tightly regulated in normal cells through proliferative arrest, apoptosis, and cellular senescence

MYC encodes

nuclear phosphoprotein that regulates growth, cell cycles, differentiation, apoptosis, and angiogenesis

c-MYC, L-MYC, N-MYC

all contain domain, N-terminal region with the MYC boxes, central region, stability control, and C-terminal with the helix-loop leucine zipper

P53

tumor suppressor, guardian of the genome; regulates DNA damage, cell cycle regulation, and apoptosis

TP53 gene family

can generate multiple transcript variants and isoforms that vary in properties → TP63 and TP73

Full length p53

393 amino acids; N-terminal transactivation domain, DNA binding central domain, C terminal tetramerization domain

Activation of RTKs Step 1

Dimerization; ligand binding causes receptor dimerization bringing the two cytoplasmic domains together and promoting activation by cross-phosphorylation at specific tyrosine residues by activated kinase domains

Adaptor/Docking Proteins

do not have kinase activity → cannot phosphorylate proteins; multi-domain structures that CAN assemble signaling networks

Adaptor/Docking Examples

Grb2, Crk, Nck, Shc

Sh2 vs Sh3 Binding

phosphotyrosine vs proline rich regions

IGF-IR Receptor

heterotetramer; two alpha subunits linked by disulfide bridges; K1003 is important for ATP binding → if mutated it cannot become activated bc it loses kinase activity

Pleckstrin Homology Domain (PH)

binds phosphorylated inositol phospholipid at membrane

Phosphotyrosine Binding Domain (PTB) and Src Homology 2 Domain (SH2)

both bind phosphotyrosine

Src Homology 3 Domain (SH3)

binds proline rich motifs (PXXP)

EphA1 binds

ephrinA1 → anti oncogenic (promotes degradation) and progranulin → oncogenic (promotes phosphorylation)

In the presence of EphrinA1 (canonical signaling)

EphA2 has desphosphorylated Ser897 → inhibition of cancer cell motility and invasion

EphrinA1-independent progranulin Akt or RSK activation (noncanonical signaling)

EphA2 phosphorylation at Ser897 → enhances EphA2 oncogenic activity

Bladder Cancer Theory

progranulin-induced MAPK and Akt-dependent EphA2 phosphorylation on S897 drives progranulin/EphA2 signaling and tumorigenesis

Ubiquitination regulates

RTK trafficking (endocytosis → clatrin-independent or clatrin-dependent)

Internalization of RTK

clatrin-coated or lipid raft → internalized in endosome → eventually degraded; surface and internal levels are equal