___ genes negatively regulate cellular growth and play
a critical role in the normal processes of the cell cycle.
Tumor suppressor genes negatively regulate cellular growth and play
a critical role in the normal processes of the cell cycle. These genes are also important for DNA repair and cell signaling.
Loss of function of ___ of a tumor suppressor gene is typically required for carcinogenesis.
Loss of function of both copies (alleles) of a tumor suppressor gene is typically required for carcinogenesis.
This functional loss of alelles from TS genes can occur via 4 mechanisms: (4)
(1) ___ gene deletion,
(2) loss of one allele and ___ of the second allele,
(3) mutational events involving __,
(4) loss of one allele and ___ of the second allele, often involving DNA ___, which suppresses expression of the gene.
1) homozygous gene deletion
(2) loss of one allele and mutational inactivation of the second allele,
(3) mutational events involving both alleles,
(4) loss of one allele and epigenetic inactivation of the second allele, often involving DNA methylation, which suppresses expression of the gene.
The “two-hit” hypothesis was first proposed in cases of retinoblastoma, which required mutations in ___ for disease manifestation
The “two-hit” hypothesis was first proposed in cases of retinoblastoma, which required mutations in both alleles for disease manifestation
T/F: specific types of mutations in certain genes may not follow the two-hit rule and can function in a dominant negative capacity when mutated, inhibiting the function of the normal protein from the unaltered allele.
An example is when two or more of the same protein molecules act together (such as ___) as is the case for __
Alternatively, deletion or mutation of a single allele may result in insufficient protein production (___), resulting in an increased carcinogen susceptibility as in the case of the CDKN1B (p27Kip1) gene
Alternatively, deletion or mutation of a single allele may result in insufficient protein production (haploinsufficiency), resulting in an increased carcinogen susceptibility as in the case of the CDKN1B (p27Kip1) gene (Fero et al., 1998).
Oncogenes are positively associated with __ and are the mutated form of normal genes (__).
Oncogenes are positively associated with cellular proliferation and are the mutated form of normal genes (proto-oncogenes).
Two oncogenes that have been found to be overexpressed in a variety of cancers include __ and ___
MYC and MET
MYC encodes an __ product that is a transcription factor responsible for regulating __. Amplification of MYC is a frequent event in __, and expression of MYC in human prostate epithelial cells has been associated with___
MYC encodes an early response gene product that is a transcription factor responsible for regulating cellular proliferation. Amplification of MYC is a frequent event in prostate cancer, and expression of MYC in human prostate epithelial cells has been associated with immortalization
___ acts through a receptor encoded by the proto-oncogene MET
Increased expression of MET has been reported in ___ and is also more frequent in higher grade cancers (Pisters et al., 1997). ____ of the MET proto-oncogene may also result in constitutive activation of the MET protein in tumors associated with hereditary renal cell carcinoma
Hepatocyte growth factor acts through a receptor encoded by the proto-oncogene MET . Increased expression of MET has been reported in renal cell carcinoma and is also more frequent in higher grade cancers. Missense mutations of the MET proto-oncogene may also result in constitutive activation of the MET protein in tumors associated with hereditary renal cell carcinoma
Mechanisms by which a proto-oncogene can be converted to
an activated oncogene are via (1) ___ of the proto-oncogene resulting in an ____ of the gene product
Mechanisms by which a proto-oncogene can be converted to
an activated oncogene are via (1) mutation of the proto-oncogene resulting in an active form of the gene product, (2) gene amplification, and (3) chromosomal rearrangement.
Immunohistochemical staining of bladder cancer specimens has demonstrated ___ in more than half of papillary and invasive tumors
Immunohistochemical staining of bladder cancer specimens has demonstrated overexpression of MYC protein in more than half of papillary and invasive tumors
chromosomal structural rearrangements such as _____ can result in the formation of an ____ for example, genetic rearrangement leading to the fusion of a portion of the TMPRSS2 gene and the ERG oncogene in a large proportion of ___cancers
chromosomal structural rearrangements such as translocation events can result in the formation of an oncogene; for example, genetic rearrangement leading to the fusion of a portion of the TMPRSS2 gene and the ERG oncogene in a large proportion of prostate cancers
In cancer, activated oncogenes and inactivated tumor suppressor genes alter the balance between these signals so that ____ is continuously favored.
___ are considered to be out of cycle in a reversible
state known as “G0, ” which is the ___ for most cells.
For cell proliferation: series of events resulting in (a) duplication of the ___ during the DNA synthetic phase (S phase), followed by (b) segregation of each genomic complement to each of ___, a process referred to as mitosis (M phase). These two critical phases are separated by two so-called “Gap” phases (__
2 resulting daughter cells
The retinoblastoma susceptibility protein, RB1 (formerly pRb), plays a central role in controlling the ___, a decision point in late G1 beyond which an __ to divide is made.
The inappropriate, continuous proliferation of cancer cells is largely due to a ___, typically the result of functional ___ of the RB1 pathway (Pardee, 1989). RB1 gene mutations have been identified in approximately one-third of ___, and reintroduction of the RB1 gene into bladder carcinoma cell lines has been found to ____
INACTIVATION OF THE RB1 PATHWAY
INHIBIT CELL GROWTH
T/F Prostate carcinoma has not been as strongly linked to RB1.
T/F Renal carcinoma has not been clearly linked to RB1.
The temporal sequencing of events occurring throughout the cell cycle is affected by a highly conserved set of protein kinases termed __
cyclin-dependent kinases, or CDKs
The enzymatic activities of the CDKs are dependent upon a class of regulatory proteins called __, so named because their ___ are tightly linked to specific phases of the cell cycle, during which they physically associate with and activate the CDK enzymatic activitY
Another group of proteins termed cyclin-dependent kinase inhibitors (CDKIs) bind to and directly ___ or their activating phosphorylations
INHIBIT CDK ACTIVITY
CDKIs belong to either of two different classes, the ____ ,broadly acting, able to inhibit multiple cyclin-CDK complexes throughout the cell cycle (Clurman and Porter, 1998), whereas the ____ are more restricted in their activities, inhibiting CDK4 and CDK6-containing complexes; thus they are critical regulators of the R-point and the G1
despite its proximity, the INK4B gene was ruled out as the primary tumor suppressor at this site because it was not within the deletion interval.
A study by Orlow et al. (1999) found that __ AND ___ of the ____ occurred frequently in superficial bladder carcinoma, but only those deletions that affect both the __ and __ genes, which are located at the same locus, correlated with a ____.
DELETION AND METHYLATION
P16 AND P14
inactivation of INK4A by ___ has been implicated in prostate cancer.
. The p16 protein binds to cyclin-dependent kinases 4 and 6 and inhibits their interaction with ___ that normally mediates passage through G1
phase of the cell cycle by phosphorylation of the ___ . The __ encoding p16 was initially found to be mutated and deleted in a wide variety of tumors including bladder and kidney
The TP53 ___ protein is a key player in cell cycle checkpoints, responding to DNA damage by signaling ___ arrest and ___ of the damage. If the ___ cannot be repaired, TP53 may trigger cell death (apoptosis). TP53 is the most commonly mutated gene in cancer and plays a prominent role in GU malignancies. TP53 was also recently found to be the most commonly mutated gene in the mutational landscape of metastatic cancer
TP53 tumor suppressor protein
cell cycle arrest and repair of the damage
Three major pathways by which DNA methylation may result in ____ in human cancer include:
(1) inherent mutational effects of ___
(2) ___ effects of promoter methylation on gene transcription
(3) potential gene activation and induction of ___ by DNA hypomethylation
The primary Th1 cytokine is ___. Th1 responses are characterized by: __, __ and __ Th1 responses are involved in viral clearance and in antitumor immune responses. Th2 responses are associated with __ and __ and generally prevent an antitumor immune response. In bladder cancer, Th2 cytokines in the urine after BCG treatment portend a __ outcome
IL-12, interferon γ and tumor necrosis factor (TNF) α
TH2 chronic inflammation and infection