Regulation Of Normal Cell Growth Research Articles

Expression of delta-lactoferrin induces cell cycle arrest.

Delta-lactoferrin (deltaLf) mRNA is the product of alternative splicing of the Lf gene. It has been found in normal tissues and was reported to be absent from their malignant counterparts. Our recent investigations have shown that deltaLf expression is a good prognostic indicator in human breast cancer. However, deltaLf has up till now only been identified as a transcript, and in order to characterize the deltaLf protein and determine its function we have used a deltaLf cDNA construct to produce the protein in vitro and in vivo. A 73 kDa protein was immunoprecipitated from in vitro translation products and this molecular weight is in accordance with the use of the first in frame AUG start codon located in exon 2. We also produced a cell line expressing deltaLf under doxycycline induction. Using this model we have been able to show that deltaLf is mainly distributed in the cytoplasm. Its expression induces cell cycle arrest and inhibits cell proliferation. Our results suggest that deltaLf may play an important role in the regulation of normal cell growth.

Expression of Fas Antigen (CD95) on Human Leukemic Cells and Assessment of Apoptosis on Fas+ and Fas-Samples by Flowcytometry Method.

Regulation of normal cell growth and turnover is balanced between cell proliferation, cell differentiation and apoptosis.A disruption of this balance is thought to be an important event leading to carcinogenesis .One of the effector molecules in apoptosis is Fas antigen . Crosslinking of Fas by its ligand (Fas L) or agonistic anti Fas antibodies induces apoptosis of cells expressing Fas on the membrane by triggering cascade of caspaces. The aim of this research was to study the percent of expression of Fas antigen on bone marrow and peripheral blood cells in 100 patients suffering from acute lymphoid and myeloid leukemia by flow cytometry method. Sample were obtained at the time of diagnosis before antileukemic therapy. Expression of Fas antigen on normal control peripheral leukocytes was also analysed. From these data, it was found that Fas antigen is expressed in all cases, but the expression level varied widely. The percentage of Fas antigen expression in all of acute lymphoid leukemia samples was below 20%, but in acute myeloid leukemia samples, 8 out of 50 cases was above 20%. In normal control samples, the mean value for monocytes was higher than granulocytes and in granulocytes higher than lymphcytes. Expression of Fas antigen in most of the leukemic cells was low and the preliminary results showed that increase in Fas antigen expression above 20% after treatment, is a favorable prognostic sign associated with increase relapse free and total survival. Thus evaluation of this antigen before, during and after treatment is recommended.

HCV core, NS3, NS5A and NS5B proteins modulate cell proliferation independently from p53 expression in hepatocarcinoma cell lines.

Several reports have shown that activity and/or expression of p53 can be modulated by Hepatitis C virus (HCV) proteins and may interfere with normal regulation of cell growth. In order to understand the relationship between p53 function and HCV proteins expression, we have investigated potential effects of the core, NS3, NS5A and NS5B proteins on Huh-7 (p53 +/+) and Hep3B (p53 -/-) cell proliferation. The effect of HCV proteins transiently expressed after recombinant-adenoviral infection was analyzed by Western blot, crystal violet and propidium iodide staining. Expression of the core, NS3, NS5A or NS5B proteins inhibited cell proliferation and blocked both cell lines in the G2/M phase of the cell cycle. c-myc and p53 expression were respectively induced and increased in Huh-7 cells only following expression of the Core protein. No expression of p21(waf1/cip1) could be detected and expression of cyclin A, cdk2 and p27(Kip1) were independent of HCV protein's expression. Our results show that the effect of core, NS3, NS5A and NS5B on cell proliferation is independent of p53 expression and that only the Core protein, induces the expression of both c-myc and p53.

Notch Activation Suppresses Fibroblast Growth Factor-dependent Cellular Transformation

Aberrant activations of the Notch and fibroblast growth factor receptor (FGFR) signaling pathways have been correlated with neoplastic growth in humans and other mammals. Here we report that the suppression of Notch signaling in NIH 3T3 cells by the expression of either the extracellular domain of the Notch ligand Jagged1 or dominant-negative forms of Notch1 and Notch2 results in the appearance of an exaggerated fibroblast growth factor (FGF)-dependent transformed phenotype characterized by anchorage-independent growth in soft agar. Anchorage-independent growth exhibited by Notch-repressed NIH 3T3 cells may result from prolonged FGFR stimulation caused by both an increase in the expression of prototypic and oncogenic FGF gene family members and the nonclassical export of FGF1 into the extracellular compartment. Interestingly, FGF exerts a negative effect on Notch by suppressing CSL (CBF-1/RBP-Jk/KBF2 in mammals, Su(H) in Drosophila and Xenopus, and Lag-2 in Caenorhabditis elegans)-dependent transcription, and the ectopic expression of constitutively active forms of Notch1 or Notch2 abrogates FGF1 release and the phenotypic effects of FGFR stimulation. These data suggest that communication between the Notch and FGFR pathways may represent an important reciprocal autoregulatory mechanism for the regulation of normal cell growth.

Expresión de la proteína p21ras en el adenocarcinoma renal localmente confinado y sus implicaciones pronósticas

ObjectiveThe p21ras protein is encoded by the three ras genes (H-, K- and N-ras) and participate in the regulation of normal cell growth and cell differenciation. The objective of this study is to determine the expression of this protein in locally confined renal cell carcinoma, as well as its relations with different histopathological variables and their prognostic implications. Method58 renal cell carcinomas, in pT1-T3a N0 M0 (TNM 1997) stages, treated by radical or partial nephrectomy with curative intention. We analysed different clinical and anatomopathological variables, as well as expression of p21ras in paraffinated tissue, using immunohistochemical techniques. ResultsThe mean percentage of stained nuclei was 6.1%, with a range lying between 0 and 45%. We did not obtain statistically significant association between expression of p21ras and the tumour size (p=0.698), the nuclear grade (p=0.676) or the histopathological stage (p=0.095). The survival analysis also did not show significant differences when we stratified the patients using the mean value of the sample as reference point (p=0.134). ConclusionsExpression of p21ras was not demonstrated to be related to any of the histopathological variables analysed: size, grade and stage, or with survival. Therefore, this protein does not appear to be related to the evolution of renal cell carcinoma.

The cell survival signal Akt is differentially activated by PDGF‐BB, EGF, and FGF‐2 in osteoblastic cells

Stimulation of osteoblast survival signals may be an important mechanism of regulating bone anabolism. Protein kinase B (PKB/Akt), a serine-threonine protein kinase, is a critical regulator of normal cell growth, cell cycle progression, and cell survival. In this study we have investigated the signaling pathways activated by growth factors PDGF-BB, EGF, and FGF-2 and determined whether PDGF-BB, EGF, and FGF-2 activated Akt in human or mouse osteoblastic cells. The results demonstrated that both ERK1 and ERK2 were activated by FGF-2 and PDGF-BB. Activation of ERK1 and ERK2 by PDGF-BB and FGF-2 was inhibited by PD 098059 (100 μM), a specific inhibitor of MEK. Wortmannin (500 nM), a specific inhibitor of phosphatidylinositol 3-kinase ( PI 3-K), inhibited the activation of ERK1 and ERK2 by PDGF-BB but not by FGF-2 suggesting that PI 3-K mediated the activation of ERK MAPK pathway by PDGF-BB but not by FGF-2. Rapamycin, an inhibitor of p70 S6 protein kinase and a downstream target of ERK1/2 and PI 3-K, did not affect the activation of ERK1 and ERK2 by the growth factors. Furthermore, our results demonstrated that Akt, a downstream target of PI 3-K, was activated by PDGF-BB but not by FGF-2. Akt activation by PDGF-BB was inhibited by PI 3-kinase inhibitor LY294002. Rapamycin had no effect on Akt activation. Epidermal growth factor (EGF) also activated Akt in osteoblastic cells which was inhibited by LY294002 but not by rapamycin. Taken together, our data for the first time revealed that the activation of ERK1/2 by PDGF-BB is mediated by PI 3-K, and secondly, Akt is activated by PDGF-BB and EGF but not by FGF-2 in human and mouse osteoblastic cells. These results are of critical importance in understanding the role of these growth factors in apoptosis and cell survival. PDGF-BB and EGF but not FGF-2 may stimulate osteoblast cell survival. J. Cell. Biochem. 81:304–311, 2001. © 2001 Wiley-Liss, Inc.

Differences in tissue-specific and embryonic expression of mouse Ceacam1 and Ceacam2 genes

The intercellular adhesion molecule CEACAM1, also known as C-CAM1 (where CAM is cell-adhesion molecule), can function as a tumour suppressor in several carcinomas, including those of the prostate, breast, bladder and colon. This suggests that CEACAM1 may play an important role in the regulation of normal cell growth and differentiation. However, there is no direct evidence to support this putative function of CEACAM1. To elucidate its physiological function by targeted gene deletion, we isolated the Ceacam genes from a mouse 129 Sv/Ev library. Although there is only one Ceacam1 gene in humans and one in rats, two homologous genes (Ceacam1 and Ceacam2) have been identified in the mouse. Our sequence analysis revealed that the genes encoded nine exons and spanned approx. 16-17 kb (Ceacam1) and 25kb (Ceacam2). The genes were highly similar (79.6%). The major differences in the protein-coding regions were located in exons 2, 5 and 6 (76.9%, 87.0% and 78.5% similarity respectively). In addition, introns 2, 5 and 7 were also significantly different, being 29.7%, 59.8% and 64.5% similar respectively. While most of these differences were due to nucleotide substitutions, two insertions of 418 and 5849bp occurred in intron 2 of Ceacam2, and another two insertions of 1384 and 197bp occurred in introns 5 and 7 respectively. To determine whether functional redundancy exists between Ceacam1 and Ceacam2, we examined their expression in 16 mouse tissues by using semi-quantitative reverse transcription-PCR. As in human and rat, in the mouse Ceacam1 mRNA was highly abundant in the liver, small intestine, prostate and spleen. In contrast, Ceacam2 mRNA was only detected in kidney, testis and, to a lesser extent, spleen. Reverse transcription-PCR using testis RNA indicated that Ceacam2 in the testis is an alternatively spliced form containing only exons 1, 2, 5, 6, 8 and 9. In the mouse embryo, Ceacam1 mRNA was detected at day 8.5, disappeared between days 9.5 and 12.5, and re-appeared at day 19. On the other hand, no Ceacam2 mRNA was detected throughout embryonic development. The different tissue expression patterns and regulation during embryonic development suggest that the CEACAM1 and CEACAM2 proteins, although highly similar, may have different functions both during mouse development and in adulthood. The Ceacam1 and Ceacam2 sequences have been deposited in the GenBank®/EMBL/DDBJ/GSDB Nucleotide Sequence Databases with accession numbers AF287911 and AF287912 respectively.

Differences in tissue-specific and embryonic expression of mouse Ceacam1 and Ceacam2 genes.

The intercellular adhesion molecule CEACAM1, also known as C-CAM1 (where CAM is cell-adhesion molecule), can function as a tumour suppressor in several carcinomas, including those of the prostate, breast, bladder and colon. This suggests that CEACAM1 may play an important role in the regulation of normal cell growth and differentiation. However, there is no direct evidence to support this putative function of CEACAM1. To elucidate its physiological function by targeted gene deletion, we isolated the Ceacam genes from a mouse 129 Sv/Ev library. Although there is only one Ceacam1 gene in humans and one in rats, two homologous genes (Ceacam1 and Ceacam2) have been identified in the mouse. Our sequence analysis revealed that the genes encoded nine exons and spanned approx. 16-17 kb (Ceacam1) and 25 kb (Ceacam2). The genes were highly similar (79.6%). The major differences in the protein-coding regions were located in exons 2, 5 and 6 (76.9%, 87.0% and 78.5% similarity respectively). In addition, introns 2, 5 and 7 were also significantly different, being 29.7%, 59.8% and 64.5% similar respectively. While most of these differences were due to nucleotide substitutions, two insertions of 418 and 5849 bp occurred in intron 2 of Ceacam2, and another two insertions of 1384 and 197 bp occurred in introns 5 and 7 respectively. To determine whether functional redundancy exists between Ceacam1 and Ceacam2, we examined their expression in 16 mouse tissues by using semi-quantitative reverse transcription-PCR. As in human and rat, in the mouse Ceacam1 mRNA was highly abundant in the liver, small intestine, prostate and spleen. In contrast, Ceacam2 mRNA was only detected in kidney, testis and, to a lesser extent, spleen. Reverse transcription-PCR using testis RNA indicated that Ceacam2 in the testis is an alternatively spliced form containing only exons 1, 2, 5, 6, 8 and 9. In the mouse embryo, Ceacam1 mRNA was detected at day 8.5, disappeared between days 9.5 and 12.5, and re-appeared at day 19. On the other hand, no Ceacam2 mRNA was detected throughout embryonic development. The different tissue expression patterns and regulation during embryonic development suggest that the CEACAM1 and CEACAM2 proteins, although highly similar, may have different functions both during mouse development and in adulthood.

The cell survival signal Akt is differentially activated by PDGF-BB, EGF, and FGF-2 in osteoblastic cells

Stimulation of osteoblast survival signals may be an important mechanism of regulating bone anabolism. Protein kinase B (PKB/Akt), a serine-threonine protein kinase, is a critical regulator of normal cell growth, cell cycle progression, and cell survival. In this study we have investigated the signaling pathways activated by growth factors PDGF-BB, EGF, and FGF-2 and determined whether PDGF-BB, EGF, and FGF-2 activated Akt in human or mouse osteoblastic cells. The results demonstrated that both ERK1 and ERK2 were activated by FGF-2 and PDGF-BB. Activation of ERK1 and ERK2 by PDGF-BB and FGF-2 was inhibited by PD 098059 (100 microM), a specific inhibitor of MEK. Wortmannin (500 nM), a specific inhibitor of phosphatidylinositol 3-kinase ( PI 3-K), inhibited the activation of ERK1 and ERK2 by PDGF-BB but not by FGF-2 suggesting that PI 3-K mediated the activation of ERK MAPK pathway by PDGF-BB but not by FGF-2. Rapamycin, an inhibitor of p70 S6 protein kinase and a downstream target of ERK1/2 and PI 3-K, did not affect the activation of ERK1 and ERK2 by the growth factors. Furthermore, our results demonstrated that Akt, a downstream target of PI 3-K, was activated by PDGF-BB but not by FGF-2. Akt activation by PDGF-BB was inhibited by PI 3-kinase inhibitor LY294002. Rapamycin had no effect on Akt activation. Epidermal growth factor (EGF) also activated Akt in osteoblastic cells which was inhibited by LY294002 but not by rapamycin. Taken together, our data for the first time revealed that the activation of ERK1/2 by PDGF-BB is mediated by PI 3-K, and secondly, Akt is activated by PDGF-BB and EGF but not by FGF-2 in human and mouse osteoblastic cells. These results are of critical importance in understanding the role of these growth factors in apoptosis and cell survival. PDGF-BB and EGF but not FGF-2 may stimulate osteoblast cell survival.

Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review).

Ovarian cancer remains the leading cause of death from gynecologic malignancy in Western countries. This cancer results from a succession of genetic alterations involving oncogenes and tumor suppressor genes which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, HER-2/neu, c-myc and K-ras, and of the tumor suppressor gene p53, have frequently been observed in sporadic ovarian cancer. In the context of high risk families, the most frequently involved genes are BRCA1 and BRCA2. We review the function of these different proteins, the incidence of mutations in their genes in carcinogenesis and as potential prognostic factors in sporadic and hereditary ovarian cancer.

Expression of a neu/c-erbB-2-like product in neuroendocrine cells of mammals.

The neu/c-erbB-2 oncogene encodes a 185 kDa protein closely homologous to the epidermal growth factor receptor. The protein product (p185) is a glycoprotein with an external domain and an internal domain with tyrosine kinase activity. Amplification and/or overexpression of p185 is related to several human adenocarcinomas. Subsequent studies demonstrated its presence in certain neuroendocrine (NE) neoplasms, including phaeochromocytomas, insulinomas and medullary thyroid carcinomas. However, relatively little is known about its role in normal cell growth regulation and development. Therefore, our objective was to determine whether neu/c-erbB-2 was expressed in normal NE tissues of different mammals, specially in humans, as it was in their neoplasms. We have examined by immunohistochemistry different endocrine glands (thyroid, pancreas, suprarrenal and hypophysis) and the small intestine of human beings, rats and guinea pigs, using two polyclonal antibodies raised against the intracytoplasmic part of the protein, and specific antigen absorption controls. We have found that a neu/c-erbB-2-like product occurs in all normal NE tissues examined: C cells of the thyroid gland, chromaffin cells of the adrenal medulla, pancreatic islets, enteroendocrine cells of the small intestine and, finally, scattered cells of the adenohypophysis, according to a typical granular immunohistochemical pattern. Our results indicate that normal NE cells share a new common antigen in their cytoplasms, a neu/c-erbB-2-like product, with a similar immunostaining pattern to that presented by the neoplasms derived from them.

Microsatellite Instability in Hematologic Malignancies

Malignant transformation in humans occurs via different mechanisms including the activation of oncogenes and/or loss of tumor suppressor genes. Recently, DNA mismatch repair defects manifest as genome wide microsatellite instability have been described as an additional mechanism of tumorgenesis in humans. Tumors exhibiting widespread microsatellite instability as first described in studies of hereditary nonpolyposis colorectal cancer (HNPCC) are referred to as having a mutator or replication error (RER+) phenotype. Until recently, the occurrence of microsatellite instability has been primarily characterized in solid neoplasms. Several reports have now identified this mutator phenotype in a number of Ieukemias and lymphomas as well. This loss of DNA replication repair function may lead to increased mutations in genes critical to normal cell growth regulation and ultimately tumor initiation and/or progression.

Inhibitors of cyclin-dependent kinase and cancer

Recent research has yielded a dramatic increase in the number of connections between oncogenesis and the proteins which regulate the cell cycle. Three classes of protein which inhibit the activity of cyclin-dependent kinases (CDKs) have emerged as potential targets for oncogenic inactivation. p16 and related proteins inhibit the cyclin/CDK complexes which regulate the transition from G1 to S phase; numerous studies have revealed that p16 is mutated in most tumor cell lines and in some types of primary tumor. p21/WAF1/Cip 1 and the related p27Kip protein inhibit a broader range of cyclin/CDK complexes than p16. Although the absence of p21/WAF1/Cip1 from cyclin/CDK complexes is correlated with cellular transformation, no mutations in this gene have been found in tumors or tumor-derived cell lines. A third class of genes which are potential targets for oncogenic inactivation are the kinases and phosphatases which regulate the activity of cyclin/CDK complexes by phosphorylation and dephosphorylation of the CDK proteins. Disruption of any of these genes would result in loss of normal regulation of cell growth.

Association of overexpression of p53 oncoprotein with the state of cell proliferation in oral carcinoma

p53 is a nuclear phosphoprotein recognised as important in the regulation of normal cell growth and proliferation, the wild-type protein suppressing cell division. Expression of presumptive mutant protein, detected by immunohistochemistry, is used increasingly as a diagnostic and prognostic marker in human neoplasms. A question arises as to whether or not p53 (over)expression in a lesion is any more or less informative than other markers of cell proliferation. Twenty well-differentiated oral squamous cell carcinomas which had earlier been examined for immunoreactivity against a panel of p53 antibodies were examined for the status of cell proliferation--both in islands of invading neoplastic cells and in the non-malignant epithelial margins. The status of epithelial cell proliferation was found to be significantly higher in p53-positive tumours when enumerated by Ki-67 antibody, both within the tumour as well as its margins. This may confer a growth advantage to these neoplasms and reflect a status of inactivated p53 protein, although the actual cause of the rapid proliferation may lie in activation/inactivation of other genes. The PCNA labelling indices, on the other hand, were closely similar in both p53-positive and -negative groups, suggesting that stabilisation of p53 protein does not influence the proliferative advantage in these carcinomas via a deregulation step of PCNA-related gene products.

Studies of the deleted in colorectal cancer gene in normal and neoplastic tissues.

Chromosome 18q is among the chromosomal regions thought to harbor a tumor suppressor gene(s) that is frequently inactivated during the development of several cancer types, particularly those of the gastrointestinal tract. Moreover, preliminary data suggest that colorectal cancers with 18q LOH have a more aggressive clinical behavior than those cancers without 18q LOH. A candidate tumor suppressor gene from 18q, termed DCC for deleted in colorectal cancer, has been identified. The DCC gene is contained within the common region of LOH on 18q, its expression is markedly decreased or absent in colorectal cancers and cell lines, and a subset of colorectal cancers have been shown to have somatic mutations within the DCC gene. Thus, DCC represents the most promising candidate tumor suppressor gene from 18q. At present, however, many questions remain regarding the mechanisms underlying the inactivation of DCC in the majority of colorectal cancers. In addition, although studies of 18q LOH and DCC gene expression in other cancer types suggest that DCC inactivation may contribute to the pathogenesis of other tumor types, few studies have provided definitive data to demonstrate that DCC inactivation is a critical genetic event in these tumors. Moreover, little is known about the function of DCC in the regulation of normal cell growth and tumor suppression. The predicted structural similarity of DCC to the N-CAM family of cell-surface proteins suggests that it may function through cell-cell and/or cell-extracellular matrix interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytogenetics and oncogenes in leukemia

Analysis of chromosomal abnormalities present in the malignant cells of patients with leukemia has provided much information of diagnostic and prognostic importance. The cloning of genes rearranged by translocation breakpoints has provided insights into both the regulation of normal cell growth and differentiation and the pathogenesis of human malignancies. This article reviews recent analyses of the association of specific karyotypic changes with other disease characteristics, including treatment outcome. Also covered is the substantial progress that has been made in the molecular analysis of genetic abnormalities in leukemia, with emphasis on those changes produced by chromosomal rearrangements. The use of information derived from these latter studies to develop polymerase chain reaction and fluorescent in situ hybridization assays for clinical use is also summarized.

Viruses and human cancer.

Epstein-Barr virus (EBV), hepatitis B virus (HBV), HTLV-I and some human papillomaviruses (HPVs) appear to contribute to the development of a large proportion of certain human cancers. Although the epidemiological evidence linking infection with these viruses to malignancies is generally convincing, only for the HPVs have experimental systems indicated a clear role for some of the HPV encoded genes in tumour cell growth. In these cases, molecular analysis is revealing the mechanisms by which the virally encoded oncogenes function to perturb the normal regulation of cell growth. For HTLV-I, EBV and HBV the mechanism by which the viruses contribute to tumour cell growth is obscure, even though much has been learned about cell transformation in culture by these viruses. A detailed understanding of the mechanism of oncogenesis will be required to design therapeutic drugs for the treatment of these cancers. Prophylactic vaccination resulting in prevention of infection may be an effective approach to reduce the incidence of some of these common cancers.

ErbB-3, a third member of the erbB/epidermal growth factor receptor gene family: its expression in head and neck cancer cell lines.

Proto-oncogenes encoding growth factor receptors constitute several distinct families with close overall structural homology. The highest degree of homology can be observed in their catalytic domains, which are essential for intrinsic tyrosine kinase activity. Growth factor receptors in several of these families play critical roles in the regulation of normal cell growth and development. Some of these molecules have been implicated in the neoplastic process as well. A related DNA fragment distinct from epidermal growth factor receptor and erbB-2 genes was detected by reduced stringency hybridization of v-erbB to normal genomic human DNA. The expression of erbB-3 was studied by southern and northern blot technique in a subset of nine head and neck tumor cell lines, as well as in three immortalized cultures established from normal human salivary glands. No gene amplification of erb-B-3 was noted in any of the head and neck cell lines. The 6.2 kb transcript of erbB-3 was elevated significantly in an epidermoid carcinoma of the larynx (A388) and an esophageal carcinoma (HA 114).

In search of the functions of normal p53 protein

p53 is of major importance in protecting cells from neoplasia. Most human tumours have an abnormal or inactivated p53 protein. Furthermore, when expression of normal p53 is reinstated in cancer cell lines, they undergo growth suppression leading to either cell differentiation or programmed cell death. But is p53 involved in the regulation of normal cell growth and differentiation in vivo? Here, Varda Rotter and colleagues critically assess some recent conflicting data on this issue.

Identification and Characterization of Novel Substrates for Protein Tyrosine Kinases

Publisher Summary This chapter discusses: (1) the strategies used to identify Protein tyrosine kinase (PTK) substrates and (2) the recent progress made in identifying new and interesting cytoskeletal protein components that serve as substrates for oncogenic PTKs. PTKS play an important role in the transmission of signals for a broad spectrum of cellular activities, including the activation of secretory events, T-cell and B-cell activation, responses to cell-extracellular matrix interactions, differentiation, mitogenesis, and oncogenesis. Because of the desire to understand the molecular basis of carcinogenesis, the roles played by PTKs in mitogenesis and oncogenesis have been most extensively studied. PTKs have also been identified as the translation products of a number of oncogenes. Expression of these tyrosine kinase oncoproteins in cultured cells results in pronounced alterations in cell shape and growth control, and in many cases, renders the transformed cells tumorigenic in syngeneic animals or nude mice. In addition, inoculation of retroviruses containing a tyrosine kinase oncogene into animals often leads to the rapid induction of leukemias or solid tumors. Thus, oncogenic PTKs subvert the regulation of normal cell growth, presumably by chronically transmitting a mitogenic signal into the cell.