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PubMed1998

Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2.

Mutations are introduced into rearranged Ig variable genes at a frequency of 10(-2) mutations per base pair by an unknown mechanism. Assuming that DNA repair pathways generate or remove mutations, the frequency and pattern of mutation will be different in variable genes from mice defective in repair. Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2. High levels of mutation were found in variable genes from XPA-deficient and PMS2-deficient mice, indicating that neither nucleotide excision repair nor mismatch repair pathways generate hypermutation. However, variable genes from PMS2-deficient mice had significantly more adjacent base substitutions than genes from wild-type or XPA-deficient mice. By using a biochemical assay, we confirmed that tandem mispairs were repaired by wild-type cells but not by Pms2(-/-) human or murine cells. The data indicate that tandem substitutions are produced by the hypermutation mechanism and then processed by a PMS2-dependent pathway.

Adenosine Triphosphatases↗
PubMed1999

Different mutator phenotypes in Mlh1- versus Pms2-deficient mice.

Deficiencies in DNA mismatch repair (MMR) result in increased mutation rates and cancer risk in both humans and mice. Mouse strains homozygous for knockouts of either the Pms2 or Mlh1 MMR gene develop cancer but exhibit very different tumor spectra; only Mlh1(-/-) animals develop intestinal tumors. We carried out a detailed study of the microsatellite mutation spectra in each knockout strain. Five mononucleotide repeat tracts at four different chromosomal locations were studied by using single-molecule PCR or an in vivo forward mutation assay. Three dinucleotide repeat loci also were examined. Surprisingly, the mononucleotide repeat mutation frequency in Mlh1(-/-) mice was 2- to 3-fold higher than in Pms2(-/-) animals. The higher mutation frequency in Mlh1(-/-) mice may be a consequence of some residual DNA repair capacity in the Pms2(-/-) animals. Relevant to this idea, we observed that Pms2(-/-) mice exhibit almost normal levels of Mlh1p, whereas Mlh1(-/-) animals lack both Mlh1p and Pms2p. Comparison between Mlh1(-/-) animals and Mlh1(-/-) and Pms2(-/-) double knockout mice revealed little difference in mutator phenotype, suggesting that Mlh1 nullizygosity is sufficient to inactivate MMR completely. The findings may provide a basis for understanding the greater predisposition to intestinal cancer of Mlh1(-/-) mice. Small differences (2- to 3-fold) in mononucleotide repeat mutation rates may have dramatic effects on tumor development, requiring multiple genetic alterations in coding regions. Alternatively, this strain difference in tumor spectra also may be related to the consequences of the absence of Pms2p compared with the absence of both Pms2p and Mlh1p on as yet little understood cellular processes.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Lack of PMS2 gene-truncating mutations in patients with hereditary colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is a genetically heterogeneous disease for which PMS2 gene, a member of the human PMS gene family, is believed to have a marginal role. To better define the contribution of PMS2 to hereditary colorectal cancer, we investigated this gene in 22 unrelated Italian patients that, despite a positive family history and/or early onset and development of tumors with microsatellite instability (MSI), did not carry constitutional mutations of MLH1 and MSH2 genes. No mutations with clear-cut pathogenetic significance were detected in the coding regions of PMS2 gene, but only 8 polymorphisms (7 common and 1 rare, 3 silent and 5 missense) and 3 unique molecular variants (2 missense substitutions and one 3-nucleotide deletion) were seen. Lack of PMS2 truncating mutations in our study does not disagree with its supposed marginal involvement in hereditary colorectal cancer, but at the same time points out the need to investigate the phenotypic molecular and clinical characteristics more specifically associated with PMS2 mutations.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Enhanced intestinal adenomatous polyp formation in Pms2-/-;Min mice.

Analysis of two human familial cancer syndromes, hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis, indicates that mutations in either one of four DNA mismatch repair gene homologues or the adenomatous polyposis coli (APC) gene, respectively, are important for the development of colorectal cancer. To further investigate the role of DNA mismatch repair in intestinal tumorigenesis, we generated mice with mutations in both Apc and the DNA mismatch repair gene, Pms2. Whereas Pms2-deficient mice do not develop intestinal tumors, mice deficient in Pms2 and heterozygous for Min, an allele of Apc, develop approximately three times the number of small intestinal adenomas and four times the number of colon adenomas relative to Min and Pms2+/-;Min mice. Although Pms2 deficiency clearly increases adenoma formation in the Min background, histological analysis indicated no clear evidence for progression to carcinoma.

Adenoma↗
PubMed1994

Mutagenesis of yeast MW104-1B strain has identified the uncharacterized PMS6 DNA mismatch repair gene locus and additional alleles of existing PMS1, PMS2 and MSH2 genes.

The haploid yeast Saccharomyces cerevisiae MW104-1B strain was disomic for chromosome III (n + 1) and carried DNA mismatches at three different heteroallelic loci; leu2 (leu2-1/leu2-27), thr4 (thr4-1/thr4-16) and his4 (his4-4/his4-519) (Williamson, 1984). We mutagenized the MW104-1B strain and identified seven mutant isolates that display elevated mitotic/meiotic prototrophs due to mismatch repair failures at heteroallelic loci. Three mutants (pms1, pms2 and pms3) isolated earlier from MW104-1B were shown to correct in vitro constructed plasmids with defined DNA mismatches (G/T, A/C, G/G, etc.) poorly (Kramer et al., 1989a). Complementation tests were performed by crossing all seven new mutant isolates to pms1 and pms2 mutants and assaying for mutant phenotype in the diploids. Four mutant isolates failed to complement the two known pms alleles (pms1-1 and pms2-1). Two other mutant isolates complemented the pms1-1 and pms2-1 alleles, but failed to complement each other and were named as the pms5-1 allele of an uncharacterized gene (PMS5). One other mutant isolate complemented the pms1-1, pms2-1 and pms5-1 alleles and was named as the pms6-1 allele of another uncharacterized gene (PMS6). Subsequently, the pms5-1 mutant allele was shown to be complemented by a plasmid borne yeast MSH2 gene, implying that it is an allele of MSH2 (PMS5). The human homologs (hMSH2 and hMLH1) of two yeast DNA mismatch repair genes (MSH2 and MLH1) have been cloned recently and shown to be responsible for hereditary nonpolypnosis colon cancer (HNPCC) (Fishel et al., 1993; Leach et al., 1993; Bronner et al., 1994; Papadopoulos et al., 1994).

Alleles↗
PubMed2000

Ionizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways.

The cytotoxicity of ionizing radiation (IR) has been associated with both the p53 pathway and with DNA mismatch repair (MMR). p53 mediates cell cycle arrest and apoptosis in response to X-ray damage, whereas the MMR complex is thought to recognize damaged bases and initiate a signal transduction pathway that can include phosphorylation of p53. To determine whether p53 and MMR mediate X-ray cytotoxicity via the same pathway, mice with targeted disruptions in either the p53 gene or the MutL homologue MMR gene Pms2 were interbred and primary fibroblasts were established from the progeny with genotypes of either wild type, p53 null, Pms2 null, or double null. Cells with either p53 or Pms2 separately disrupted showed reduced levels of apoptosis after IR in comparison with wild type, but the double null cells showed even lower levels, consistent with nonoverlapping roles for p53 and PMS2 in the X-ray response. In transformed cell lines established from the primary cells at early passage, similar differences in the apoptotic response to IR were seen, and clonogenic survival assays following low dose rate IR further showed that nullizygosity for Pms2 confers increased survival on cells in both wild-type and p53 null backgrounds. These results indicate that both p53 and MMR contribute to X-ray-induced apoptosis and that the role of MMR in the cytotoxicity of IR does not depend on p53.

Animals↗
PubMed2006

Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance.

Inherited defects in genes associated with DNA mismatch repair (MMR) have been linked to familial colorectal cancer. Cells deficient in MMR are genetically unstable and demonstrate a tolerance phenotype in response to certain classes of DNA damage. Some sporadic human cancers also show abnormalities in MMR gene function, typically due to diminished expression of one of the MutL homologs, MLH1. Here, we report that overexpression of the MutL homolog, human PMS2, can also cause a disruption of the MMR pathway in mammalian cells, resulting in hypermutability and DNA damage tolerance. A mouse fibroblast cell line carrying a recoverable lambda phage shuttle vector for mutation detection was transfected with either a vector designed to express hPMS2 or with an empty vector control. Cells overexpressing hPMS2 were found to have elevated spontaneous mutation frequencies at the cII reporter gene locus. They also showed an increase in the level of mutations induced by the alkylating agent, methynitrosourea (MNU). Clonogenic survival assays demonstrated increased survival of the PMS2-overexpressing cells following exposure to MNU, consistent with the induction of a damage tolerance phenotype. Similar results were seen in cells expressing a mutant PMS2 gene, containing a premature stop codon at position 134 and representing a variant found in an individual with familial colon cancer. These results show that dysregulation of PMS2 gene expression can disrupt MMR function in mammalian cells and establish an additional carcinogenic mechanism by which cells can develop genetic instability and acquire resistance to cytotoxic cancer therapies.

Adenosine Triphosphatases↗
PubMed2005

A role for Pms2 in the prevention of tandem CC --> TT substitutions induced by ultraviolet radiation and oxidative stress.

DNA mismatch repair (MMR) is important for preventing base-pair substitutions caused by spontaneous or damage-related DNA polymerase errors. We have used a reversion assay based on mouse Aprt to investigate the role of MMR in preventing ultraviolet radiation (UV) and oxidative stress induced tandem CC --> TT base pair substitutions in cultured mammalian cells. The reversion construct used for this assay can detect both C --> T and CC --> TT mutational events. Most spontaneous mutations in Pms2-deficient cells were single C --> T substitutions (88%), with the remainder being tandem CC --> TT substitutions (12%). The percentage of tandem CC --> TT substitutions rose to 64% and 94% for Pms2-deficient cells exposed to UV and a mixture of hydrogen peroxide and metals (Cu/Fe), respectively. Exposure to hydrogen peroxide alone or metals alone did not induce the tandem substitutions, nor did treatment of the cells with the alkylating agent ethylmethane sulfonate, which induces G --> A substitutions on the opposite strand. Tandem CC --> TT substitutions were also induced by UV irradiation and the hydrogen peroxide/metal mixture in Pms2-proficient cells, but at frequencies significantly lower than those observed in the Pms2-deficient cells. We conclude that mismatch repair plays an important role in preventing tandem CC --> TT substitutions induced by certain genotoxin exposures.

Adenine Phosphoribosyltransferase↗
PubMed2000

Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.

Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote. The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.

Adenoma↗
PubMed2005

Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.

We report the clinicopathological, genetic, and immunohistochemical characterization of an atypical Turcot syndrome (TS) family with small bowel cancer. The tumor family history of a patient with cafè-au-lait spots (CALS) and early onset adenomas, duodenal cancer, and glioblastoma was positive for colonic adenoma (mother), jejunal (maternal grandfather), lung (father), and colorectal (paternal uncle) cancers. PMS2 genetic testing identified the nonsense 1951C>T (Q643X) and the missense 161C>T (S46I) mutations. PMS2 expression was absent in the proband's duodenal cancer with high microsatellite instability. The normal cells also displayed no PMS2 expression and some degree of instability. Our findings point out the association between PMS2 and TS, and support the hypothesis that patients with a few polyps, small bowel tumors with a very early onset, glioblastoma, and CALS should be considered as a variant of hereditary nonpolyposis colorectal cancer. A recessive model of inheritance caused by compound heterozygous mutations was consistent with the observed severe clinical phenotype and has important implications for predicting cancer risk in both the proband and his relatives.

Adenosine Triphosphatases↗
PubMed2003

Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

DNA mismatch repair maintains genomic stability by detecting and correcting mispaired DNA sequences and by signaling cell death when DNA repair fails. The mechanism by which mismatch repair coordinates DNA damage and repair with cell survival or death is not understood, but it suggests the need for regulation. Since the functions of mismatch repair are initiated in the nucleus, we asked whether nuclear transport of MLH1 and PMS2 is limiting for the nuclear localization of MutLalpha (the MLH1-PMS2 dimer). We found that MLH1 and PMS2 have functional nuclear localization signals (NLS) and nuclear export sequences, yet nuclear import depended on their C-terminal dimerization to form MutLalpha. Our studies are consistent with the idea that dimerization of MLH1 and PMS2 regulates nuclear import by unmasking the NLS. Limited nuclear localization of MutLalpha may thus represent a novel mechanism by which cells fine-tune mismatch repair functions. This mechanism may have implications in the pathogenesis of hereditary non-polyposis colon cancer.

Active Transport, Cell Nucleus↗
PubMed2004

Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer.

PURPOSE: Immunohistochemistry (IHC) and microsatellite instability (MSI) analysis can be used to identify patients with a possible DNA mismatch repair defect [hereditary nonpolyposis colorectal carcinoma (HNPCC)]. The Bethesda criteria have been proposed to select families for determination of MSI. The aims of this study were to assess the yield of MSI analysis in families suspected for HNPCC, to compare the results of immunohistochemical staining and MSI analysis, and to assess the additional value of PMS2 staining. EXPERIMENTAL DESIGN: Clinical data and tumors were collected from 725 individuals from 631 families with suspected HNPCC. MSI analysis was performed using eight markers including the 5 National Cancer Institute markers. Four immunohistochemical staining antibodies were used (MLH1, MSH2, MSH6 and PMS2). RESULTS: A MSI-H (tumors with instability for >30% of the markers) phenotype in colorectal cancers (CRCs) was observed in 21-49% of families that met the various Bethesda criteria. In families with three cases of CRC diagnosed at age > 50 years, families with a solitary case of CRC diagnosed between ages 45 and 50 years, and families with one CRC case and a first-degree relative with a HNPCC-related cancer, one diagnosed between ages 45 and 50 years (all Bethesda-negative families), the yield of MSI-H was 10-26%. Immunohistochemical staining confirmed the MSI results in 93% of the cases. With IHC, adding PMS2 staining led to the identification of an additional 23% of subjects with an hMLH1 germ-line mutation (35 carriers were tested). CONCLUSIONS: The Bethesda guidelines for MSI analysis should include families with three or more cases of CRC diagnosed at age > 50 years. The age at diagnosis of CRC in the original guidelines should be raised to 50 years. Routine IHC diagnostics for HNPCC should include PMS2 staining.

Adenosine Triphosphatases↗
PubMed2005

Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC).

A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories.

Adaptor Proteins, Signal Transducing↗
PubMed2002

A:T --> G:C base pair substitutions occur at a higher rate than other substitution events in Pms2 deficient mouse cells.

The mismatch repair pathway involves multiple proteins that are required to correct DNA polymerase generated mismatches before they become mutations. It has been shown recently, that the predominant base-pair substitution events leading to loss of endogenous Aprt activity in Pms2 null mouse cells are A:T --> G:C mutations (Oncogene 21 (2002) 1768, Oncogene 21 (2002) 2840). To determine if this observation could be explained by an increased rate of A:T --> G:C mutations relative to other base-pair substitutions, we developed a reversion assay to examine G:C --> A:T, C:G --> A:T, and A:T --> G:C mutations within mouse Aprt in a Pms2 null mouse kidney cell line. The results demonstrated a 6-50-fold increase in the rate of the A:T --> G:C mutations relative to the other base-pair substitutions. Additional work demonstrated that growth of the Pms2 null cells in antioxidant containing medium reduced the rate of the A:T --> G:C mutations. The results are discussed with regards to the role of mismatch repair proteins in preventing base-pair substitutions, including those induced by oxidative stress.

Adenosine Triphosphatases↗
PubMed2001

Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination.

Isotype switching involves a region-specific, nonhomologous recombinational deletion that has been suggested to occur by nonhomologous joining of broken DNA ends. Here, we find increased donor/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can occur by microhomology-mediated end-joining. Interestingly, although isotype switching and somatic hypermutation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nucleotide substitutions generated during somatic hypermutation. This finding is in contrast to MSH2 deficiency. With MSH2, the altered pattern of switch recombination and hypermutation suggests parallels in the mechanics of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may reflect differences in the pathways of break resolution.

Adenosine Triphosphatases↗
PubMed2002

Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions.

B cells from mice deficient in mismatch repair (MMR) proteins show decreased ability to undergo class switch recombination in vitro and in vivo. The deficit is not accompanied by any reduction in cell viability or alterations in the cell cycle in B cells cultured in vitro. To assess the role of MMR in switching we examined the nucleotide sequences of Smicro-Sgamma3 recombination junctions in splenic B cells induced in culture to switch to IgG3. The data demonstrate clear differences in the sequences of switch junctions in wild-type B cells in comparison with Msh2-, Mlh1-, and Pms2-deficient B cells. Sequences of switch junctions from Msh2-deficient cells showed decreased lengths of microhomology between Smicro and Sgamma3 relative to junctions from wild-type cells and an increase in insertions, i.e., nucleotides which do not appear to be derived from either the Smicro or Sgamma3 parental sequence. By contrast, 23% of junctions from Mlh1- and Pms2-deficient cells occurred at unusually long stretches of microhomology. The data indicate that MMR proteins are directly involved in class switching and that the role of Msh2 differs from that of Mlh1 and Pms2.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse.

Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of Escherichia coli MutL heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. Although MLH1/PMS2 is generally thought to have the major MutL activity, the precise contributions of each MutL heterodimer to mismatch repair functions are poorly understood. Here, we show that Mlh3 contributes to mechanisms of tumor suppression in the mouse. Mlh3 deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, Mlh3;Pms2 double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from Mlh1-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role for Mlh3 in gastrointestinal and extragastrointestinal tumor suppression. The data also suggest a mechanistic basis for the more severe mismatch repair-related phenotypes and cancer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice. Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair-mediated tumor suppression, therefore, provide an explanation why, among MutL homologues, only germ line mutations in MLH1 are common in hereditary non-polyposis colon cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Alterations in PMS2, MSH2 and MLH1 expression in human prostate cancer.

DNA mismatch repair (MMR) is involved in the post-replication correction of errors due to misincorporated nucleotides or DNA slippage during DNA synthesis. We previously reported the reduction or loss of MMR protein expression in human prostate cancer cell lines and some primary tumors. In the present report, we further demonstrate the involvement of defects of MMR in the pathogenesis of prostate cancer. Immunohistochemical analysis of 39 formalin-fixed, paraffin-embedded human prostate tumors, showed reduction or absence of MMR protein expression (MLH1, MSH2, PMS2) in the epithelium of prostate tumor foci compared to normal adjacent prostate tissue. The reduction or absence of the PMS2 and MSH2 (but not MLH1) protein was correlated to the differentiation of the tumor. Poorly differentiated tumors showed greater loss of these two proteins than the well differentiated tumors (P<0.05). We previously reported that microsatellite instability was detectable by a beta-galactosidase restoration mutation assay in the prostate cancer cell lines DU145, PC3, LNCaP, p67SV40T, M2182, and M12. In this study, we detected the insertion or deletion of one nucleotide in the mononucleotide repeats located within the coding regions of BAX gene in DU145, and TGFbetaRII in M12 cells. In addition, we used an in vitro model of defective MMR to demonstrate that microsatellite instability can be induced in an otherwise stable cancer cell line by transfection with a dominant negative fragment of PMS2. These results suggest that defects in MMR may result in MSI in the secondary genes in prostate cancer. From these results, we conclude that loss of MMR function can produce MSI and target some secondary genes containing microsatellites in their coding regions. These series of events may play important roles in the development of human prostate cancer.

Adaptor Proteins, Signal Transducing↗