As with RB, normal p53 also can be rendered nonfunctional by certain oncogenic DNA viruses. Proteins encoded by oncogenic HPVs, certain polyoma viruses, and hepatitis B virus bind to p53 and nullify its protective function. Thus, transforming DNA viruses subvert two of the best-understood tumor suppressors, RB and p53.
TP53: GUARDIAN OF THE GENOME
TP53 encodes p53, the central monitor of stress in the cell, which can be activated by anoxia, inappropriate oncogenesignaling, or DNA damage. Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNArepair, cellular senescence, and apoptosis.
DNA damage leads to activation of p53 by phosphorylation. Activated p53 drives transcription of CDKN1A (p21), whichprevents RB phosphorylation, thereby causing a G1-S block in thecellcycle.ThispauseallowsthecellstorepairDNAdamage.
IfDNAdamagecannotberepaired,p53inducescellularsenescenceorapoptosis.
Ofhumantumors,70%demonstratebiallelicmutationsinTP53.PatientswiththerareLi-FraumenisyndromeinheritonedefectivecopyofTP53 inthegermline,suchthatonlyoneadditionalmutationisrequiredtolosenormalp53function.Li-Fraumenisyndromepatientsarepronetodevelopawidevarietyoftumors.
AswithRB,p53canbeincapacitatedwhenboundbyproteinsencodedbyoncogenicDNAvirusessuchasHPV.
Although much is known about the circuitry that applies brakes to the cell cycle, the molecules that transmit anti-proliferative signals to cells are less well characterized. Best-known is TGF-β, a member of a family of dimeric growth factors that includes bone morphogenetic proteins and activins. In most normal epithelial, endothelial, and hematopoietic cells, TGF-β is a potent inhibitor of proliferation. It regulates cellular processes by binding to a complex composed of TGF-β receptors I and II. Dimerization of the receptor upon ligand binding leads to a cascade of events that result in the transcriptional activation of CDKIs with growth-suppressing activity, as well as repression of growth-promoting genes such as MYC and CDK4.