Biomedical subjects

Michael S Serfas

Publications and source records attributed to Michael S Serfas.

6 recordsLinked to original sources

PubMed2005

Pharmacologic approaches to butterfly wing patterning: sulfated polysaccharides mimic or antagonize cold shock and alter the interpretation of gradients of positional information.

Butterflies produce complex and diverse wing patterns by mechanisms that are generally unknown. We have employed a pharmacological approach to explore the molecular mechanisms of pattern formation. In a screen of over 200 compounds injected into developing Junonia coenia pupae, we identified several specific sulfated polysaccharides that caused widespread, dose-dependent effects on adult wing patterns. These compounds were well tolerated and permitted butterflies to eclose normally and take flight at moderate levels of effect. Heparin and closely related chondroitin sulfates caused stage-specific expansion of distal and proximal band systems and reduction and repatterning of eyespots. Dextran sulfate and fucoidan, whose structures are widely divergent from heparin and one another, caused contraction of distal and proximal systems, but had no effect on eyespots. Nonsulfated or nonpolymeric saccharides were without effect. Pattern alterations were indistinguishable from those reported for extreme cold shock and exposure to sodium tungstate and "molsin". When administered after cold shock or coinjected with heparin, dextran sulfate reversed all patterning effects. We suggest that the primary effect of polysaccharide treatments is to alter the interpretation of gradients of positional information along the proximodistal axis of the pupal wing.

Animals↗

PubMed2004

A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues.

p21WAF1/CIP1 is an important transcriptional target of p53 and it plays a critical role in growth arrest after DNA damage. Here, we report the identification of a novel alternate mouse p21 transcript that is conserved in evolution. It differs from the classical p21WAF1/CIP1 transcript in the first exon, which is located at approximately 2.8 kb upstream of transcriptional start site of p21WAF1/CIP1 and is sandwiched between two p53 binding sites. This novel p21 transcript is present in most mouse tissues with highest levels of expression in the spleen. In contrast to the classical p21WAF1/CIP1 transcript, this new transcript is highly dependent on p53 for its basal expression, as evidenced by its absence in nearly all of p53-/- mouse tissues. This transcript is also absent at nonpermissive temperature in a 10-1 mouse cell line lacking endogenous p53 and harboring temperature-sensitive p53 mutant. However, this novel transcript is induced to appreciable levels in the presence of high p53 activity at the permissive temperature. Our data suggest that p53-dependent induction of p21 may be an additive effect conferred by individual increases in the alternate and classical p21 transcripts.

Animals↗

PubMed2004

Butterfly wing pattern evolution is associated with changes in a Notch/Distal-less temporal pattern formation process.

In butterflies there is a class of "intervein" wing patterns that have lines of symmetry halfway between wing veins. These patterns occur in a range of shapes, including eyespots, ellipses, and midlines, and were proposed to have evolved through developmental shifts along a midline-to-eyespot continuum. Here we show that Notch (N) upregulation, followed by activation of the transcription factor Distal-less (Dll), is an early event in the development of eyespot and intervein midline patterns across multiple species of butterflies. A relationship between eyespot phenotype and N and Dll expression is demonstrated in a loss-of-eyespot mutant in which N and Dll expression is reduced at missing eyespot sites. A phylogenetic comparison of expression time series from eight moth and butterfly species suggests that intervein N and Dll patterns are a derived characteristic of the butterfly lineage. Furthermore, prior to eyespot determination in eyespot-bearing butterflies, N and Dll are transiently expressed in a pattern that resembles ancestral intervein midline patterns. In this study we establish N upregulation as the earliest known event in eyespot determination, demonstrate gene expression associated with intervein midline color patterns, and provide molecular evidence that wing patterns evolved through addition to and truncation of a conserved midline-to-eyespot pattern formation sequence.

Animals↗

PubMed2003

The Cdk inhibitor p21 is required for necrosis, but it inhibits apoptosis following toxin-induced liver injury.

Liver injury and repair were examined in wild type, p21Waf1/Cip1, and p27Kip1-deficient mice following carbon tetrachloride (CCl4) administration. In wild type liver, p21 expression is induced in a biphasic manner following injection of CCl4, with an early peak of p21 expression occurring in pericentral hepatocytes at 6 h, prior to evidence of injury, and a second peak succeeding regenerative proliferation. In contrast, p27 is present throughout the quiescent liver, but its expression decreases following CCl4 injection. Surprisingly, p21-deficient animals were resistant to CCl4-induced necrotic injury, indicating that rapid induction of p21 in pericentral hepatocytes following CCl4 injection contributes to subsequent necrosis. Expression of cytochrome P450 2E1, which plays an essential role in CCl4-induced necrotic injury, was not affected in p21-deficient mice. Although they had the least injury, p21-deficient mice had the highest levels of hepatic proliferation that correlated with increases in hyperphosphorylated retinoblastoma protein and Cyclin A gene expression. Increased replication in p21-deficient livers was counteracted by an increase in hepatocyte apoptosis as detected by caspase-3 activation. p21 plays distinct and opposing roles regulating hepatocyte survival during injury and subsequent repair, with early induction of p21 contributing to necrotic injury and later expression to cessation of proliferation and hepatocyte survival.

Alanine Transaminase↗

PubMed2003

Brk, Srm, Frk, and Src42A form a distinct family of intracellular Src-like tyrosine kinases.

The tyrosine kinases Brk/PTK6/Sik, Srm, Frk/Rak/Gtk/Iyk/Bsk, and Src42A/Dsrc41 have a low degree of sequence homology to other known kinases, including one another. We show here that the exon structure of these kinases, which we will call the Brk family, is highly conserved and distinct from each of the major families of intracellular kinases containing SH3, SH2, and tyrosine kinase domains, including c-Src and Fyn. Brk/Sik and Srm are 1.1 kb apart on human chromosome 20q13.3 and likely are the result of duplication in cis. Several Brk family kinases have an inhibitory effect on Ras pathway signaling from receptor tyrosine kinases. Members of this family can act either in the membrane or at the nucleus, and may change localization patterns depending on external stimuli. Brk has been shown to phosphorylate two proteins in vivo: Sam68. a substrate for Src in mitosis that can substitute for Rev in nuclear export of RNAs; and BKS, a novel adaptor molecule. Brk also functions as a rapid downstream signaling intermediate following calcium-induced differentiation in keratinocytes. It is possible that Brk family kinases may share common functions and interaction partners, which remain for the most part unexamined.

Animals↗

PubMed2002

P21 functions to maintain quiescence of p27-deficient hepatocytes.

Hepatocytes rarely proliferate in the healthy adult liver. We explored the roles of the cyclin kinase inhibitors p21 and p27 in maintaining hepatocyte quiescence. p27 is expressed throughout the wild-type liver, but the related protein p21 was not detected. However, p21 was detected in livers of p27-deficient mice. Increased p21 protein levels did not result from an increase in p21 mRNA expression, indicating that p21 expression is regulated post-transcriptionally. p21 protein levels increased in cultured primary hepatocytes treated with the proteasome inhibitor MG132 and cycloheximide, indicating that p21 expression is regulated at the level of protein stability in liver cells. Although increased expression of cyclin-dependent kinase (Cdk) 4, Cdk2, and proliferating cell nuclear antigen was detected in p27-deficient livers, increased hepatocyte proliferation was detected only in livers of mice deficient for both p21 and p27. In p27-deficient livers, p21 was found in complexes with Cdk2 and CdK4 and can compensate for the absence of p27. Our data indicate that cyclin kinase inhibitor activity is important for maintaining hepatocyte quiescence in the adult liver. Significant increases in p21 were detected in multiple tissues of mature p27-deficient mice compared with wild-type mice, suggesting that the ability of p21 to functionally substitute for p27 is not liver-specific.

Animals↗