Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants

Greenblatt, Marc S.; Beaudet, Julie; Gump, Jay; Godin, Katherine S.; Trombley, Lucy; Koh, James; Bond, Jeffrey P.

doi:10.1038/sj.onc.1206101

Cited by 70 publications

(96 citation statements)

References 21 publications

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“…It has been shown previously that disease mutations are generally not distributed at random among amino acid sites within genes (for example, Botstein & Risch, 2003;Greenblatt et al 2003;Miller & Kumar, 2001;Mooney & Klein, 2002;Notaro et al 2000). Instead, disease-causing mutations are generally overabundant at evolutionarily conserved sites.…”

Section: Testing For the Distribution Of Human Mutations Using The Inmentioning

confidence: 99%

“…Recent literature clearly underscores the importance of understanding human disease mutations from an evolutionary perspective (Botstein & Risch, 2003). Therefore, this second test is necessary because there is a known overabundance of disease mutations at evolutionarily conserved amino acid sites (Greenblatt et al 2003;Miller & Kumar, 2001;Mooney & Klein, 2002;Notaro et al 2000), thus illustrating the importance of conserved residues in the proper functioning of protein products.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying the Intragenic Distribution of Human Disease Mutations

Miller

Parker²,

Rissing³

et al. 2003

Annals of Human Genetics

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SummaryA wide variety of functional domains exist within human genes. Since different domains vary in their roles regarding overall gene function, the ability for a mutation in a gene region to produce disease varies among domains. We tested two hypotheses regarding distributions of mutations among functional domains by using (1) sets of single nucleotide disease mutations for six genes (CFTR, TSC2, G6PD, PAX6, RS1, and PAH) and (2) sets of polymorphic replacement and silent mutations found in two genes (CFTR and TSC2). First, we tested the null hypothesis that sets of mutations are uniformly distributed among functional domains within genes. Second, we tested the null hypothesis that disease mutations are distributed among gene regions according to expectations derived from the distribution of evolutionary conserved and variable amino acid sites throughout each gene. In contrast to the mainly uniform distribution of sets of silent and polymorphic mutations, sets of disease mutations generally rejected the null hypotheses of both uniform and evolutionary-influenced distributions. Although the disease mutation data showed a better agreement with the evolutionary-derived expectations, disease mutations were found to be statistically overabundant in conserved domains, and under-represented in variable regions, even after accounting for amino acid site variability of domains over long-term evolutionary history. This finding suggests that there is a nonadditive influence of amino acid site conservation on the observed intragenic distribution of disease mutations, and underscores the importance of understanding the patterns of neutral amino acid substitutions permitted in a gene over long-term evolutionary history.

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Section: Testing For the Distribution Of Human Mutations Using The Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantifying the Intragenic Distribution of Human Disease Mutations

Miller

Parker²,

Rissing³

et al. 2003

Annals of Human Genetics

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“…The deleted sequence is located in the first ankyrin repeat and encodes an evolutionarily conserved 6 amino acids (LEAGAL). 28 Deletions and mutations affecting these amino acid have been reported in melanomas and other cancers and shown to significantly affect the CDK-and cell cycleinhibitory activities of p16…”

Section: Mutation Analysis and Expression Of Wild-type Ink4amentioning

confidence: 99%

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Rotolo

Diotti

Gordon

et al. 2005

Intl Journal of Cancer

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Activating BRAF mutations and loss of wild-type INK4A expression both occur at high frequencies in melanomas. Here, we present evidence that BRAF and INK4A have different effects on melanogenesis, a marker of melanocytic differentiation. Human melanoma cell line 624Mel harbors mutations in both BRAF and INK4A. The in vitro and in vivo growth of these cells was inhibited by either reduced expression of mutant BRAF using stable retroviral RNA interference (RNAi) or retrovirus-mediated stable expression of wild-type INK4A cDNA. Consistent with the observed growth inhibition, phosphorylation of S780 and S795 in pRB, both CDK4/6 targets, was suppressed in cells expressing either mutant BRAF RNAi or wild-type INK4A. Interestingly, melanoma cells expressing mutant BRAF RNAi had increased pigmentation, produced more mature melanosomes and melanin and expressed higher levels of tyrosinase and tyrosinase-related protein-1, whereas melanogenesis was not induced by wild-type INK4A. We found that the melanocyte lineage-specific master control protein microphthalmia-associated transcription factor was upregulated by inhibition of mutant BRAF, which may be the cause for the melanogenic effect of BRAF RNAi. The results suggest that, although both BRAF and INK4A lesions promote cell growth and tumor formation, mutant BRAF may also induce dedifferentiation in melanoma cells. ' 2005 Wiley-Liss, Inc. Key words:T1796A BRAF; INK4A; melanogenesis; differentiation; melanoma Melanoma is becoming one of the most prevalent malignancies with a dismal prognosis. Further understanding of melanoma biology is required to design better strategies in the treatment of this devastating disease. BRAF mutations have been identified in 70% of human malignant melanomas.1 A T1796A transversion in axon 15, resulting in a V599E substitution in the BRAF kinase domain, accounts for >90% of BRAF mutations detected in melanoma samples.1 BRAF is a component of the RAS-RAF-MEK-ERK signaling pathway that plays essential roles in cell proliferation, differentiation and survival.2 BRAF is one of 3 members of the RAF family, 2 which are serine/threonine kinases that transduce regulatory signals from RAS through MEK to ERK.V599E BRAF has increased kinase activity; causes intrinsic ERK activation in cultured NIH3T3 cells, COS cells and human melanocytes; and leads to elevated transforming activity of cultured NIH3T3 cells and human melanocytes.1,3-5 Suppression of V599E BRAF expression has been reported to cause inhibition of melanoma cell proliferation and survival in vitro and in vivo. 6-8Apart from BRAF mutation, most melanoma cells have lost expression of wild-type INK4A, through either DNA deletion/mutation or promoter hypermethylation.9-12 INK4A encodes the cell cycle regulator p16INK4A , which binds to and inhibits CDK4/6 and promotes cell cycle arrest via the RB tumor-suppressor pathway.13,14 Consistent with a tumor-suppressor role of INK4A in melanomas, a germline R24C mutation in CDK4 has been identified in familial melanoma patients. 15,16 This mutation ...

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“…This portion of ARF was believed to be dispensable because ectopic expression of the N-terminal half of ARF is sufficient to fulfill all known functions of full-length ARF, 6,8,11 and the chicken ortholog p7 ARF , which lacks the exon2-derived C-terminal half, displays most, if not all, of the known functional attributes of its mammalian counterparts. 12 Nevertheless, why the 5' portion of the exon2 that is shared by p16 and ARF is preferentially attacked by cancer mutations, 3,[13][14][15] especially by those that affect only ARF but not p16, has remained unexplained. Genetic evidences have demonstrated that mice lacking functional ARF, Mdm2 and p53 together are more tumor-prone than those lacking both Mdm2 and p53, indicating that ARF has growth inhibitory functions independent of Mdm2 and p53.…”

mentioning

confidence: 99%