Tumor suppressor genes | Anatomy2Medicine
Tumor Suppressor Genes Cell Cycle

Tumor suppressor genes

    • Tumor suppressor genes

 

  • RB

 

        • tumor suppressor gene
        • Patients with familial retinoblastoma are also at greatly increased risk of developing osteosarcoma and other soft-tissue sarcomas. (MCQ)
        • Knudson “two-hit” hypothesis of oncogenesis. (MCQ)
          • Two mutations (hits), involving both alleles of RB at chromosome locus 13q14, are required to produce retinoblastoma. (MCQ)
          • In some cases, the genetic damage is large enough to be visible in the form of a deletion of 13q14.
          • In familial cases, children inherit one defective copy of the RB gene in the germ line (one hit); the other copy is normal

 

  • Retinoblastoma develops when the normal RB allele is mutated in retinoblasts as a result of spontaneous somatic mutation (second hit).
  • Because only a single somatic mutation is required for loss of RB function in retinoblastoma families, familial retinoblastoma is inherited as an autosomal dominant trait.

 

          • In sporadic cases both normal RB alleles must undergo somatic mutation in the same retinoblast (two hits).

 

  • Loss of heterozygosity(MCQ)

 

          • A child carrying an inherited mutant RB allele in all somatic cells is perfectly normal (except for the increased risk of developing cancer).
          • Because such a child is heterozygous at the RB locus, this implies that heterozygosity for the RB gene does not affect cell behavior.
          • Cancer develops when the cell becomes homozygous for the mutant allele or, put another way, when the cell loses heterozygosity for the normal RB gene (a condition known as LOH,). (MCQ)
        • other genes that act similarly as RB gene

 

  • genes on the short arm of chromosome 11 (MCQ)

 

          • play a role in the formation of Wilms’ tumor, hepatoblastoma, and rhabdomyosarcoma
        • von Hippel-Lindau (VHL) gene (MCQ)
          • a tumor suppressor gene that causes familial clear cell renal carcinomas
      • RB protein is the product of the RB gene
      • It is a ubiquitously expressed nuclear phosphoprotein that plays a key role in regulating the cell cycle(MCQ)
      • RB exists in an
        • active hypophosphorylated state in quiescent cells
        • inactive hyperphosphorylated state in the G1/S cell cycle transition (MCQ)
  • How will RB protein controls G1/S cell cycle transition
        • The initiation of DNA replication requires the activity of cyclin E–CDK2 complexes(MCQ)
        • expression of cyclin E is dependent on the E2F family of transcription factors(MCQ)
        • Early in G1, RB is in its hypophosphorylated active form, and it binds to and inhibits the E2F family of transcription factors, preventing transcription of cyclin E.
      • Rb also controls the stability of the cell cycle inhibitor p27. (MCQ)
    • RB stimulates myocyte-, adipocyte-, melanocyte-, and macrophage-specific transcription factors.

 

  • germline loss or mutations of the RB gene predispose to occurrence of (MCQ)
  • retinoblastomas
  • osteosarcomas.
  • glioblastomas, small-cell carcinomas of lung

 

    • breast cancers, and bladder carcinomas.
  • p53: Guardian of the Genome.
      • p53 gene is located on chromosome 17p13.1(MCQ)
      • it is the most common target for genetic alteration in human tumors(MCQ)
      • As with the RB gene, inheritance of one mutant allele predisposes individuals to develop malignant tumors
      • Double hit leads to  Li-Fraumeni syndrome(MCQ)
        • the most common types of tumors are sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal cortex.

 

  • p53 acts as a “molecular policeman” that prevents the propagation of genetically damaged cells. (MCQ)

 

      • p53 gene product
        • it is a transcription factor that is at the center of a large network of signals that sense cellular stress, such as DNA damage, shortened telomeres, and hypoxia
        • As with RB, the transforming proteins of several DNA viruses, including the E6 protein of HPV, can bind to and promote the degradation of p53. (MCQ)

 

  • MDM2 and MDMX (MCQ)

 

    • gene that regulates p53 function
    • stimulate the degradation of p53
    • these proteins are frequently overexpressed in malignancies in which the gene encoding p53 is not mutated
    • MDM2 is amplified in 33% of human sarcomas, thereby causing functional loss of p53 in these tumors(MCQ)

 

      • p53 thwarts neoplastic transformation by three interlocking mechanisms:
        • activation of temporary cell cycle arrest (quiescence)
        • induction of permanent cell cycle arrest (senescence),
        • triggering of programmed cell death (apoptosis).

 

  • Stressed cell vs Unstressed cell

 

        • In nonstressed, healthy cells, p53 has a short half-life (20 minutes), because of its association with MDM2, a protein that targets it for destruction. (MCQ)
        • When the cell is stressed, for example by an assault on its DNA, p53 undergoes post-transcriptional modifications that release it from MDM2 and increase its half-life. (MCQ)
      • miRNAs

 

  • p53 activates transcription of the mir34 family of miRNAs (mir34a–mir34c) (MCQ)

 

        • mir34 microRNAs are able to recapitulate many of the functions of p53 and are necessary for these functions,
        • Targets of mir34s include
          • pro-proliferative genes such as cyclins,
          • anti-apoptotic genes such as BCL2

 

  • regulation of this miRNA is crucial for the p53 response.
  • How will  p53 senses DNA damage and determines the adequacy of DNA ?

 

        • key initiators of the DNA-damage pathway are two related protein kinases:
          • ataxia-telangiectasia mutated (ATM) (MCQ)

 

  • ataxia-telangiectasia and Rad3 related (ATR) (MCQ)

 

        • Once triggered, both ATM and ATR phosphorylate a variety of targets, including p53 and DNA-repair proteins.

 

  • p53-mediated cell cycle arrest

 

        • considered the primordial response to DNA damage
        • It occurs late in the G1 phase (MCQ)
        • caused mainly by p53-dependent transcription of the CDK inhibitor CDKN1A (p21).
        • p21 prevents cells from entering G1 phase
          • inhibits cyclin-CDK complexes
          • inhibits phosphorylation of RB
        • p53 induces certain proteins, such as GADD45 (growth arrest and DNA damage), that help in DNA repair
      • p53 can stimulate DNA-repair pathways by transcription-independent mechanisms as well.
        • If DNA damage is repaired successfully, p53 up-regulates transcription of MDM2, leading to its own destruction and thus releasing the cell cycle block.
        • If the damage cannot be repaired, the cell
          • may enter p53-induced senescence
          • undergo p53-directed apoptosis.

 

  • p53 directs the transcription of several pro-apoptotic genes such as BAX and PUMA
  • p53 mutations and cancer treatment resistance

 

        • testicular teratocarcinomas and childhood acute lymphoblastic leukemias
          • Tumors that retain normal p53 are more likely to respond to  therapy than tumors that carry mutated alleles of the gene.
        • lung cancers and colorectal cancers
          • Tumors that carry p53 mutations, are relatively resistant to chemotherapy and irradiation.

 

  • p53p63-p73 network(MCQ)

 

      • p63 is essential for the differentiation of stratified squamous epithelia
      • p73 has strong pro-apoptotic effects after DNA damage induced by chemotheraputic agents.
    • APC/β-Catenin Pathway.

 

  • Adenomatous polyposis coli genes (APC)

 

        • represents a class of tumor suppressors whose main function is to down-regulate growth-promoting signals.
        • Germ-line mutations at the APC (5q21) loci are associated with familial adenomatous polyposis, (MCQ)
        • both copies of the APC gene must be lost for a tumor to arise.
      • APC is a component of the WNT signaling pathway, which has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development (MCQ)
        • An important function of the APC protein is to down-regulate β-catenin. In the absence of WNT signaling, APC causes degradation of β-catenin, preventing its accumulation in the cytoplasm.[
        • Signaling by WNT blocks the APC-AXIN-GSK3β destruction complex, allowing β-catenin to translocate from the cytoplasm to the nucleus.
        • In the cell nucleus, β-catenin forms a complex with TCF, a transcription factor that up-regulates cellular proliferation by increasing the transcription of c-MYC, cyclin D1, and other genes.
      • What happens with  inactivation of the APC gene ? (MCQ)
        • It disrupts the destruction complex, of Beta catenin
        • β-catenin survives and translocates to the nucleus, where it can activate transcription in cooperation with TCF
        • cells with loss of APC behave as if they are under continuous WNT signaling.
      • Dysregulation of the APC/β-catenin pathway is seen in

 

  • colon cancers
  • hepatoblastomas
  • hepatocellular carcinomas

 

        • Tumor Suppressor genes

 

  • Cell surface
  • TGF-β receptor

 

        • Growth inhibition
        • Carcinomas of colon

 

  • E-cadherin

 

        • Cell adhesion
        • Carcinoma of stomach
        • Familial gastric cancer

 

  • Inner aspect of plasma membrane
  • NF1

 

        • Inhibition of RAS signal transduction and of p21 cell cycle inhibitor
        • Neuroblastomas
        • Neurofibromatosis type 1 and sarcomas

 

  • Cytoskeleton
  • NF2

 

        • Cytoskeletal stability
        • Schwannomas and meningiomas
        • Neurofibromastosis type 2 acoustic schwannomas, and meningiomas

 

  • Cytosol
  • APC/β-catenin

 

        • Inhibition of signal transduction
        • Carcinomas of stomach, colon, pancreas; melanoma
        • Familial adenomatous polyposis coli/colon cancer
      • PTEN PI3 kinase

 

  • signal transduction

 

        • Endometrial and prostate cancers
        • Cowden syndrome
      • SMAD2 and SMAD4 (MCQ)

 

  • TGF-β signal transduction

 

        • Colon, pancreas tumors
        • Nucleus

 

  • RB1
  • Regulation of cell cycle

 

        • Retinoblastoma; osteosarcoma carcinomas of breast, colon, lung
        • Retinoblastomas, osteosarcoma
      • p53
        • Cell cycle arrest and apoptosis in response to DNA damage
        • Most human cancers
        • Li-Fraumeni syndrome; multiple carcinomas and sarcomas
      • WT1

 

  • Nuclear transcription

 

        • Wilms’ tumor
      • P16/INK4a
        • Regulation of cell cycle by inhibition of cyclin dependent kinases
        • Pancreatic, breast, and esophageal cancers
        • Malignant melanoma
      • BRCA1 and BRCA2(MCQ)

 

  • DNA repair

 

    • Carcinomas of female breast and ovary
    • carcinomas of male breast