Sh3 Sh2 Sh1

DNA bind actin bind

SH1: Tyr Kinase

NLS: Nuclear localisation signal

Figure 3.3.12.B. Structure of ABL. The protein comprises 1130-1143 amino acids. Functional domains include SH3 (binds BP1 to inhibit SH1 activation), SH2, SH1 (with a tyrosine that is subject to autophosphorylation), a nuclear localization domain, a DNA-binding domain, and an Actin-binding domain. Note that the form 1b (but not the alternatively spliced form 1a) is myristylable allowing anchorage to the membrane. [Reprinted from Atlas Genet Cytogenet Oncol Haematol. October 1997. Huret JL. ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1). With permission from Atlas.]

• Cyclin Dj/CDK4 kinase activity is elevated in various cancers, including breast cancer, head and neck cancer, hepatocellular carcinoma, and colorectal carcinoma, either through the overproduction of Cyclin Dj or through mutations in cdk4, which makes Cyclin Dj/CDK4 insensitive to the inhibitory effects of P16INK4a. Furthermore, the tumor suppressor protein P16INK4a is itself commonly mutated in certain cancers. It is the only INK4 homolog strongly implicated in carcinogenesis.

• In squamous cell carcinoma, CDK6, normally a target of P16 may be affected. This leads to unchecked inactivation of the RB tumor suppressor. The overexpression of CDK6 mediates accelerated progression through G1, dependent on its NH2-terminal INK4 interaction domain.

• Most tumors harbor dysregulations of the E2F family of transcription factors, resulting in abnormal cell cycle progression. This may occur as a consequence of the loss of the CDKI P16INK4a, the overexpression of Cyclin D, or the loss of RB. The apoptotic activity of E2F1 reflects, at least in part, its ability to transactivate the promoters of p73 and p53.

• RIZ-1 (Retinoblastoma-Interacting Zinc Finger Protein) is a tumor suppressor and a member of the Histone/Protein Methyl Transferase superfamily. riz1 inactivation commonly arises in diffuse large B-cell lymphomata, breast cancers, and liver cancers. It occurs through DNA hypermethylation, frameshift mutations, chromosomal deletion, or missense mutations.

• Truncating mutations and homozygous deletions in the SNF5 (INI1, BAF47) subunit of SWI/SNF complexes occur in most malignant rhabdoid tumors [Biegel et al. 2002].

• The concomitant loss of the SWI/SNF ATPase subunits SMARCA4 (BRG-1) and BRM occurs in approximately 10% of non-small lung cancers. This is associated with a reduced life expectancy.

• A common chromosome translocation in CML leads to the formation of the oncogenic fusion protein BCRABL. The BCRABL oncoprotein strongly associates with F-Actin. The formation of BCR-ABL oligomers is permissive for the simultaneous binding of multiple F-Actin filaments (Figure 3.3.12.C).

3.3.13 The P53 pathway

P53 has a domain structure with a transactivation domain (amino acids 1-101), a sequence specific DNA-binding domain (amino acids 102-292), an oligomerization domain (amino acids 320-360), and a region for inhibition of sequence-specific binding (amino acids 363-393) (Figure 3.3.13.A).

- P53 recruits the basal transcriptional machinery through the transactivation domain (amino acids 1-101). It interacts with TBP (TATA Box Binding Protein) and TAF (TBP-Associated Factor, a component of TFII-D). P53 contains a nuclear export signal in amino acids 11 through 27. Phosphorylation in this region correlates with reduced nuclear export of P53. The oncoprotein MDM2 (an E3 Ubiquitin Ligase with a RING finger motif) binds to the NH2-terminal region of P53 and thus inhibits its transactivating activity.

- P53 binds to the consensus nucleotide sequence (A/G)(A/G)(A/G)C(A/T)(A/T)G(C/T)(C/T)(C/T) (P53 responsive element) as a tetramer. The DNA-binding domain of P53, from amino acid

Figure 3.3.12.C. Philadelphia chromosome. Generation of the Philadelphia chromosome is associated with more than 95% of chronic myelogenous leukemias (CML). Normal representations of chromosome 9 and 22 are displayed on the left. The right side shows the rearranged chromosomes, where the c-abl proto-oncogene from the distal tip of chromosome 9q34 has been translocated into the bcr (breakpoint cluster region) locus on chromosome 22q11.2. This t(9;22) translocation generates a chimeric gene that expresses a chimeric bcr-abl mRNA, yielding a fusion protein. [Reproduced from Life_Science/Cancer_Research/Key_Resources/Overvie w_of_Cancer_Biology.html. There are instances where we have been unable to trace or contact the copyright holder. If notified the publisher will be pleased to rectify any errors or omissions at the earliest opportunity.]

a p53 N

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